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A personal journey of discovery of the role of oxygen tension, bone remodeling units, and mesenchymal stem cells in orthopedic disorders, repair and bone tumors initiated after a torn medial meniscus of the left knee terminated my collegiate basketball career.

      My undergraduate biology program at Duke University emphasized embryology, fetal development, functions of ectoderm, mesoderm {having multipotential cells also capable of forming bone, cartilage, adipocytes, and fibrous stroma} and endoderm and the role of the apical epidermal ridge in determining fetal limb elongation and number of digits. During early limb development, initial low oxygen tension causes the axial mesoderm to form a central cartilage model of future limb bones. A relatively higher oxygen tension in the amniotic fluid bathes the peripheral tissues of the developing fetal limb. The oxygen tension dramatically increases when vessels immigrate from the base of the developing limb to supply the developing soft tissue structures of the limb. The vascular supply nourishes the peripheral mesenchymal elements in the initial layer of the chondrogenic periosteum causing it to transform and form the osteogenic layer of the periosteum that applies the initial lamina of cortical bone to the surface of the centrally located cartilage model.

       Primary ossification centers in the cartilaginous center of the diaphysis and of the epiphyseal ends of a developing bone are created by invasion of vessels whose endothelial lining cells are presumably attracted by low oxygen tension present in the centrally located cartilage model.

      As the diaphyseal nutrient vessel arises in the soft tissue of the mid-diaphysis, its endothelial cells are presumably attracted by the low oxygen tension in the central cartilage model. This arterial vessel enters the center of the cartilage model of the diaphysis. After entering the cartilage model, this artery divides into proximal and distal branches. Each branch then gives rise to smaller vascular beds whose marginal vessels give rise to peripheral bone remodeling units (BRUs) that remove mineralized ischemic cartilage and deposit bone matrix.

      Osteoclasts emerging from vessels in the vascular bed of a remodeling unit replace the axial, i.e., central, mineralized cartilage model, while creating a central medullary cavity that retains its the hypoxic state as compared to that of the vascularized soft tissues on the surface of the developing bone model. The enlarging medullary cavity becomes filled with mesenchymal cells that also line the outer surface of the walls of the vessels that were involved in creation of the medullary cavity. While most of the mesenchymal cells filling the medullary cavity differentiate into adipocytes, a few mesenchymal cells, which that an earlier time in my biology classes were called “resting cells”, remained randomly distributed among the adipocytes. These inactive cells were later called mesenchymal stem cells (MSCs). Their purpose is to initiate structural repair following future local structural damage. During bone development the mesenchymal cells present in the medullary cavity also form a fibrillar stroma that houses hematopoietic cells of yolk sac origin as hematopoietic bone marrow elements arrive from the blood in the new medullary vessels. Mesenchymal cells at the periphery of the medullary cavity differentiate into osteoblasts that form the endosteal lining of the medullary cavity.

      Vascular beds arise from the ends of the proximal and distal branches of diaphyseal nutrient arteries. Bone remodeling units (BRUs) that arise from the activated endothelial cells of small peripheral vessels progressively replace the proliferating linear columns of chondrocytes. Those columns of chondrocytes result from serial interstitial division of chondrocytes that increase the length of the bone model.

       By the time of skeletal maturity, vascular invasion followed by endochondral ossification has replaced the cartilage models of both epiphyses with cancellous bone. The newly formed epiphyseal cancellous bone subsequently merges with the cancellous bone of the remodeled metaphases following closure of the growth plates of the diaphysis.

      During growth in length of a long bone, the periosteum forms and applies serial layers of cortical bone that entrap between them a longitudinally oriented vascular supply. The resulting linear array of longitudinally oriented vessels are interconnected laterally to superficial vessels on the periosteal surface and to deeper arrays of longitudinal vessels located between serial cortical bony lamina by transversely oriented vessels passing through Volkmann canals.   

      During postnatal growth and beginning with initiation of weightbearing, bone modeling begins as new patterns of bone deposition are formed to resist applied mechanical forces, i.e., more bony laminae are formed on the dorsomedial cortical surfaces of the diaphysis of paired limb bones to reflect increasing axial body weight, i.e., center of gravity. Mechanical weight-bearing forces also stimulate the formation of cortical bone remodeling units (CBRUs).

      The leading component of the osteon-bone-forming unit of a CBRU is called a “cutting cone”. It consists of a vascular loop whose leading end is covered by osteoclasts that emerge as mononuclear cells of hematopoietic origin from the blood in the vascular lumen. The trailing component of the vascular loop is called the “filling cone”. The surface of the smooth muscle wall of the vascular loop is covered by a layer of mesenchymal cells that differentiate into osteogenic cells. The resulting osteoblasts apply bone matrix to mineralized surfaces of pre-existing bone or cartilage that have been excavated by osteoclasts of the cutting cone. These new cylinders of bone contain a central vessel that is a remnant of the vessel of the cutting cone. Osteocytes entrapped in bone matrix originate from osteoblasts deposited by the osteoprogenitor cells on the surface of the filling cone. These cylindrical bone units that are inserted between concentric lamina of cortical bone are called “osteons”. The inserted osteons provide increased bone density and add compressive strength to cortical bone.

      Bone surface remodeling units (BSRUs) also have unique structural features. BSRUs are attracted to mineralized bone surfaces, e.g., endosteal surface of the medullary cavity and surfaces of cancellous bone, perhaps by ischemia and/or mechanical forces. The BSRU initially applies a small sheet of osteoclasts to a focal area of a bone surface. Each osteoclast in the sheet removes a shallow depression in the bone surface called a “resorption pit”. Together with other osteoclasts in the sheet, the resorption pits form a “resorption bay”.                                                                                                       

       After the initial phase of surface excavation has been completed, the BSRU covers the surface of the resorption bay with a sheet of contiguous mesenchymal cells that differentiate into osteoblasts. This sheet of osteoblasts may apply one to several layers of lamellar bone to the surface of the resorption bay while entrapping themselves as “osteocytes”.  Osteocytes entrapped in each bone layer have thin cytoplasmic processes that maintain connections with similar thin cytoplasmic cell processes of adjacent osteoblasts and those osteoblasts immediately overlying their layer and to osteocytes buried more deeply. Subsequently, this cellular sheet of osteogenic cells establishes a canalicular-lacunar system that functions not only in calcium homeostasis but also in maintaining mechanical support.

      Growth plates are also called physes. They are located at the ends of the diaphysis of a bone. Their remodeling begins with the penetration of the distal zone of mineralized cartilage in the growth plate by a cutting cone of a bone remodeling unit (BRU). The cutting cone penetrates and removes the transverse septa between serially aligned necrotic chondrocytes in a zone of mineralized columns of degenerative chondrocytes. The filling cone applies a layer of bone to the denuded mineralized cartilage surface of the columns of empty chondrocyte lacunae to form an initial trabecula of primary cancellous bone. The centrally located mineralized layer of cartilage matrix in the primary cancellous trabecula has then been covered by bone.

       In the Spring of my senior year at Duke University and prior to gradation, I received a letter of acceptance for graduate training in a university medical orthopedics laboratory. However, my life was to be changed forever when two weeks later, I received a letter from my Draft Board indicating the date that I was to report for induction into the US Military Service soon after graduation.

      This adventure was not without rewards. After basic training, and as a college graduate with reading skills in two foreign languages, I qualified for training in cryptography at US Army Signal Crop Headquarters where I was informed that my code machine was worth more than my life. For nearly the next three years of my life, I attempted to send messages or interpret messages consisting of random patterns of letters, numbers, and symbols. After two brief overseas assignments, I was assigned to the US Air Defense Command presumably to protect the US Naval Facility in the Philadelphia area during the Cold War with Russia.

      While I was stationed in the Philadelphia area, I met a tennis companion who introduced me to thoroughbred horse racing at the several racetracks in that area. He accompanied me into the training sheds where I made friends with several equine trainers and their veterinarians who encouraged me to examine the limbs of their horses. With them I discussed limb anatomy and my then limited understanding of the causes of lameness. As a result, my companion, who was a veterinary oncology surgeon in the vet school at U. Penn, inspired me to become a veterinarian and to pursue a career that enabled me to investigate athletic injuries in horses and small animals. Following an honorable discharge, I applied for and was accepted to veterinary school.

      During veterinary training in my second year at Oklahoma State University College of Veterinary Medicine, two radiologists and a pathologist remarked on my apparently precocious ability to interpret radiographs and to quickly recognize altered patterns of normal structure that indicated their cause. All three remarked that my interpretative skills in radiology likely reflected my prior years of military experience where I attempted to interpret patterns of letters, numbers, and symbols as a cryptographer. The veterinary training program encouraged hands-on clinical examination of limbs of lame animals. Because of my interest in orthopedic disease, the faculty recommended me for a combined residency/graduate PhD training program in the Pathology Department UCD School of Veterinary Medicine.

      Faculty in the UCD SVM Pathology Department recognized my interest in orthopedic disease and bone tumors; so, they added an informal semi-residency tutorial in orthopedic radiology to my general pathology residency program. Near the end of my residency training, the department offered me a future faculty position if I would take a 2-year post-doc training program in transmission and scanning electron microscopy. I eagerly accepted that opportunity.

      Two years later and after I returned to the department as an assistant professor, I helped establish a new EM lab shared with the Anatomy Department of the vet school. TEM was useful in my investigations of certain bone disorders in cats including feline viral osteochondromatosis that was caused by a c-retro virus. I soon found interpretation of SEM images most helpful in recognizing unique patterns of bone destruction caused by inflammatory cell exudate, carcinomas, and different types of sarcomas. Subsequently, I was invited to share this new information in a seminar that I presented at the Armed Forces Institute of Pathology in Washington, D.C. One of the attendees at my seminar was Lent C. Johnson, MD, Director of the Medical Orthopedics Division. After my seminar Dr. Johnson invited me to remain a few days with him and visit his laboratory.  There he shared with me his unique insights into the mechanisms that create different patterns of healing in damaged bones and joints as well as the causes of different radiographic patterns produced by the human body’s response to bone tumors.

      In addition to departmental academic roles in providing lectures and labs for small animal and equine bone disorders, I was the VMTH musculoskeletal pathologist for animal patients and for related collaborative clinical research.

      Early in my career at UCD SVM I was asked by a senior faculty member to add a chapter on bone tumors to a new edition of his book on animal tumors. At that time there was no published classification system for bone tumors in domestic animals. Anticipating that request, I had already spent nearly a year reviewing H&E-stained tissue sections and radiographs of musculoskeletal tumors in our departmental files. This review included several hundred bone tumors of small animals and a few large animals. From that collection I attempted to match the animal bone tumors with those published by David Dahlin, MD at the Mayo Clinic, Rochester. Minn. as the then currently accepted standard classification for bone tumors in man. I called Dr. Dahlin to ask his permission to use his classification of bone tumors for my chapter. During our conversation, he invited me for a slide review session at his office. I spent a 2-day weekend with him, and he agreed that my tumor selections were compatible with his classification. As I was leaving to return to Davis, he thanked me for sharing my collection with him and seemed amused with my adaption of his classification scheme for animals. Therefore, this was the first published classification of bone tumors of domestic animals. Ref. Pool. R.R. Tumors of bone and cartilage. In Tumors of Domestic Animals., 3rd. ed. J.E. Moulton, ed. University of California Press, Berkeley. 1990.

      Subsequently, I was invited to the AFIP to be a member of an international committee whose mission was to create and publish an animal bone tumor classification for The World Health Organization. The committee adapted my previously published animal bone tumor classification. I became a Co-author of “WHO Classification of Bone and Joint Tumors of Domestic Animals”, 1994.

      A new 12yr-long adventure began early in my 25yr-long departmental career. In addition to my already busy academic duties, our dean appointed me as the bone & bone marrow pathologist for a new US Department of Energy “Lifespan Study of Irradiation Effects of Ra226 & Sr90 on 1200 beagle dogs” that was being conducted at our campus UCD Radiobiology Laboratory. I was joined in this collaborative research effort by the faculty radiologist who had provided my radiology training as a pathology resident. Together we were tasked to demonstrate to the DOE medical review board that was composed of 2 physicians who specialized in radiation effects and 3 radiobiologists that the beagle dog is a good model for the investigating and reproducing the known effects of Ra226 in young girls and women known as radium dial painters. If the results of the Ra226 study were valid, then the beagle would serve as a “presumptive model’ for anticipating the effects in humans due to Sr90 falloutfrom current widespread open-air A-bomb testing. The DOE reviewers also made two requirements. First, we were to document comparative radiographic and histopathologic images as evidence for similar biological effects in both species, i.e., in young female radium dial painters and in the DOE Ra226 irradiated beagles. Second, our report was to use medical terminology.

      My colleague and I accomplished the first request. During two occasions we paid three-day-long visits to the Argonne National Laboratory in Illinois. There we were given access to a repository that contained the terminal radiographs and H&E-stained bone sections of necropsy specimens of several of these young girls and women, i.e., “Dial Painters”. We made photographic images of the radiographic abnormalities and histologic images of bone lesions that were present at their death. After our return home we compared selected Beagle radiographic and microscopic bone images of radiation effects and tumor induction in beagles to those in the young female radium dial painters. Comparative images from radiographs and histopathology sections from the skeletons of the beagles and young female radium dial painters were similar.

      The additional request for comparative terminology in our descriptive reports as required by the DOE reviewers prompted the director of the UCD Radiobiology Laboratory to send me for training in medical terminology to the AFIP in Washington, DC.  There, I was greeted by my former mentor, Lent C. Johnson, MD, who was director of the medical orthopedics division at the AFIP. He had me attend 3 courses in medical orthopedic diseases and bone tumors in 3 age groups of humans that he presented at Gorge Washington University College of Medicine for physicians preparing to serve in orthopedic units of the 3 branches of the US Military. Thereafter, comparative descriptions of skeletal lesions in our reports covering the lifespan study of irradiation effects of Ra226 in beagles met the approval of the DOE reviewers in both our periodic summary reports and in the final report of this 12-year study.

      The comparative DOE sponsored study using beagle dogs was designed to mimic the known Ra226 hotspot bone distribution pattern in the skeletons of the mostly teenage girls known as “Radium Dial Painters”. The hotspot skeletal distribution pattern in the girls resulted from their oral ingestion of Ra226 while licking and tipping watercolor brushes dipped in a solution containing Ra226 while they painted dials on watches. Any bone formed and deposited in these mostly immature young women contained Ra226.

      Immature beagles, whose ages approximated that of late teenage girls, received their Ra226 by IV administration at intervals that were determined by protocol to mimic bone deposition patterns like those in the late teenage dial painters. In both groups “hotspot” distribution occurred in the bones of both species where CBRUs formed osteons that had incorporated Ra226 and where BSRUs acting on endosteal,and other bone surfaces had excavated those surfaces and deposited new layers of bone that incorporated Ra226. Therefore, similar patterns of hotspot distribution including newly labeled osteonal bone were created in both species. According to protocol, the several different dose groups of beagles were housed in kennels. There they received good nutrition, excellent health care and had routine physical exams that included radiographs. Beagles were euthanized for sample collection according to protocol.

      According to protocol in the Ra226 beagle study, clinical radiographs of more than 250 dogs were examined that had received serial IV administrations of Ra226 at specified intervals. For the main study, protocol determined the locations for routine bone samples. Some samples were selected for thin-section radiography, microradiography, and histopathologic examination. Findings were recorded for reports. All radiographic lesions having radiographic features of bone tumors were photographed and bone sections were taken for histopathologic interpretation. Images and interpretations were recorded.

      As an orthopedic pathologist, I was, of course, curious about the cause of spontaneous bone tumors in domestic canine pets and as well as the cause of bone tumors that arose following the administration of Ra226 and Sr90 in the experimental beagle dogs. My inquiry was not part of the mission of the DOE sponsored project. However, I wanted to understand the pathogenesis of the Ra226-induced “hotspot” bone lesions and the role of the “hotspot “in the development of malignant bone tumors in beagle dogs.

      This adventure originated from our observations that many beagle radiographs had several unique, thin, i.e., 1-2 mm diameter, linear (1 cm to several cm-long) hyperdense streaks. Several linear streaks had one or more tiny, i.e., 2-3 mm diameter, focal cavitations along the length or at their end of the streak. A few of the linear radiodense radiographic streaks had even larger focal cavitations, i.e., 4-5 mm diameter. A few of the larger focal cavitations were irregular in shape and appeared to arise by coalescing of adjacent smaller cavitations. These findings were best appreciated when selected specimens containing the radiographic streaks that had been observed in clinical radiographs were cut in longitudinal and in transverse planes. These thin bone sections were examined initially as high detailed radiographic images and then by selection as micro radiographic images. These bone specimens were then decalcified to prepare H&E-stained bone sections for histologic examination.

     Examination of the role of Ra226 in the forming radiation-induced hotspots, i.e., recognized as gray hyperdense radiographic streaks, were found to be created by infarcted osteons. The microcavities observed along the length or end of a streak were caused by an infarcted osteon that was undergoing excavation by a CBRU. In many microcavities MSCs of CBRUs were engaged in new bone deposition following removal of ischemic osteonal bone. These tiny cavities were found to be sites of active bone remodeling created by CBRUs that arose from viable vessels that emerged from a Volkmann canal. The vessel from the Volkmann canal that supplied a CBRU arose from an adjacent vessel was present either between a viable bony cortical lamina or from a Haversian vessel. Larger cavitations were formed by the entry of more than one CBRU whose vascular supply emerged from vessels located in Volkmann canals. Vessels supplying BRUs arose from viable longitudinally oriented vessels in the fatty marrow near the endosteal surface.

      Several larger micro cavitary lesions, only a few mm in size, contained a spectrum of contents that on histologic examination ranged from granular fragments of necrotic bone debris without viable cells to those that contained fibrillar stroma having viable cells and capillaries. Several cavitary lesions were filled with proliferative fibro-osseous stroma containing a few polygonal cells that contained one or two mitotic figures. The contents of these cavities suggested early neoplastic transformation of MSCs in the repair tissue of activated CBRUs. A few of the larger cavities contained polygonal cells sharing features with low grade pleomorphic bone tumors. Similar histologic features were a minor finding in primary bone tumors of irradiated beagles, i.e., primarily osteosarcomas that arose in many of the high dose level groups in the Ra226 experimental beagles.

      Observations of sections that sampled gray radiographic streaks in several bones concluded that there appeared to be no significant effect of irradiation by Ra226 infusion on the formation, and initial function of CBRUs and their blood supply at the time of their formation because the initial BRUs formed osteons having normal histologic features that only after formation developed a necrotic central vessel and necrotic osteocytes. This finding indicated that it was the chronic exposure of radiation from Ra226 deposited in the bone matrix of the osteons that killed its central Haversian vessel and the buried osteocytes and caused infarction of the osteons.

      Question then arose as to the role of Ra226 in bone tumor formation. Since bone tumors appeared to arise from neoplastic transformation of MSCs of activated CBRUs that were attracted as repair units to a focal site of decreased oxygen tension created by an infarcted osteon, did neoplastic transformation of MSCs occur due to radiation from Ra226 or did neoplasia result only from the effects of the low oxygen tension on MSC repair cells?

      The question concerning the role of bone infarction in the pathogenesis of bone tumors in irradiated beagles is not easily resolved by examining their bone specimens. This dilemma is because primary bone tumors in many domestic dogs arise at sites of remodeling bone infarcts. In these domestic dogs, an idiopathic arteriopathy of a branch of a nutrient artery causes bone and bone marrow infarction. Focal decrease in oxygen tension in the infarcted tissue activates MSC repair cells. In some infarcts, MSC repair cells undergo neoplastic transformation and form a “spontaneous” bone tumor. I recently published a report on the findings from my collection of amputated limbs of 653 domestic canine pets all of which had bone infarcts of medullary cavity of a long bone caused by an arteriopathy. “Canine Idiopathic Arteriopathy, Appendicular Bone Infarcts, and Neoplastic Transformation of Bone Infarcts in 108 Dogs. Comp. Medicine”. DOI: 10.30802/AALAS-CM-22-000037.

      In 52% (59 of 114) of these domestic dogs, ischemia of the infarcted fatty marrow activated the resting MSCs. In this groupthe activation process resulted in “reparative infarcts”. By comparison, ischemic activation resulted in neoplastic transformation of MSCs in 48% (55 of 114) in this group of dogs and produced a spectrum of neoplasia ranging from pleomorphic sarcoma to the several subtypes of osteosarcoma. The findings in that report indicate why canine pets have 27 times more bone tumors than occur in man.

      An adventure in dental pathology occurred because 15% of the body burden of Sr90 is in the dentine of the teeth of the 250 beagles that had received body burdens of Sr90. The Sr90 deposits irradiated the adjacent alveolar bone and gingivaA spectrum of more than 200 reactive dental lesions and tumors occurred in these dogs. Those lesions and tumors mimicked histologically similar spontaneous dental lesions and tumors in man.

      As the veterinary pathologist for that study, my radiobiology lab director arranged for me to participate in specimen review sessions with 2 MD oral pathologists and 3 DDS dental pathologists where I received a tutorial in medical oral/dental pathology. Both the medical and dental reviewers were interested in these apparent radiation-induced dental lesions. While these dental lesions were from beagles, all reviewers commented on the histologic similarities of the dental specimens in the beagles to spontaneous counterparts in man. Subsequently, this experience also proved useful in my newly acquired training in diagnosis of spontaneous dental lesions and tumors in VMTH patients. However, this opportunity added a time-consuming role for me since I immediately became the vet school’s dental pathologist in addition to my already busy academic life.

      My adventure in the Ra226 and Sr90 12yr-long Beagle investigation terminated after necropsy of the last control beagle, but I was soon to be invited by the dean to participate in another adventure that was closer to my personal and professional interests.

       Two years later, the dean appointed me to be the UCD SCVM pathologist for what was to be an 8yr.-long “Study of Catastrophic Breakdown Injuries in California Racehorses”. Animal rights groups were exerting political pressure on the State of California Horseracing Board and the horseracing industry to reduce the number of euthanasia’s of racing TB’s due to nonrepairable forelimb injuries encountered during racing and training. As a joint venture, I participated with the California Animal Health and Diagnostic Laboratory System by examining the injured limbs of racehorses euthanized because of breakdown injuries. Horses euthanized at both Northern and Southern California racetracks were transported to local branches of the state livestock diagnostic laboratories. There their carcasses underwent a general necropsy examination that also included testing for race-performance-enhancing medication. Both forelimbs from a horse euthanized for a breakdown lesion were delivered to me by a special currier to the branch of the state diagnostic laboratory located adjacent to the UCD VMTH.

      Both legs were examined because the sound leg had experienced the same repetitive mechanical forces as by the injured leg during training and racing. Injuries were photographed during gross limb dissections. The injured bone and the counterpart bone in the opposite sound limb were then brought to the pathology lab in the VMTH where orthogonal radiographs were taken of both bones. Radiographic images of the bone in the injured limb were used to determine the approach for dissection.

      While longitudinal bone growth in a TB has ceased by about 3 years of age, skeletal maturation is not complete until about 6 years of age. As 2- and 3-year-old thoroughbred horses begin to train and encounter increasing cyclic compression especially to the cortices of long bones of the forelimbs, modeling of the craniomedial cortex of MCIII increases as does an increase in the activation of the accompanying CBRUs.

      Catastrophic racing injuries occur often in skeletally immature horses that are 3 to 5 years of age. By comparison this is somewhat analogous to 15- to 18-year-old boys training for and racing in Olympic 1500-meter events. By examining the same location in the bone of the sound leg as the site of multiple fracture fragments in the bone of the injured leg, we found evidence of early stages of developing stress fractures. Some of the micro fissures were in the early stages of repair by BMUs. Upon reassembling and sampling the fracture fragments of the injured bone, we commonly found remnants of stress fracture lines and evidence of BMU repair in one or more of those fracture fragments that precipitated catastrophic cortical bone fragmentation. Comminution of the fracture resulted in limb failure.

      By coordinating our investigation with epidemiologists who inquired as to the training history of horses that sustained a catastrophic breakdown injury, we learned that several of the affected horses had a history of “stall rest” for several days to a few weeks because of unrelated disorders prior to their “early” return to racing and limb failure. These were young horses that had suddenly been taken out of training and/or racing and essentially had “bedrest”, or “stall rest’” without exercise. Even the few that had had swimming pool exercise during the rest period that while maintaining cardiovascular and pulmonary function, did not exert mechanical forces sufficient to maintain athletic bone structure.

      Apparently, due to the abrupt cessation of exercise and a resulting failure to maintain the prior athletically modeled bone structure, the absence of mechanical loading appears to have activated BMUs. Once activated the BMUs initiated a modeling process of the inactive long bones of both forelimbs apparently in a biological attempt to return of the bone to its pre-athletic state. Perhaps due to financial pressure from the horse’s owner or owners of the rested horse, the trainer accelerated the horse’s return to a race-training and racing too rapidly after a rest period. A failure to resume intense and progressive training which involves repetitive mechanical impaction on bone and their joint surfaces in preparation for a return to racing apparently initiates loss of bone structure.  Extended disuse activates retrograde bone modeling not unlike bone loss from disuse due to inactivity or because from loss of gravity encountered by astronauts that predisposes in racehorses to the development of stress fracture and occurrence of catastrophic breakdown.

      The positive results of our findings provided financial incentives for racetrack management to purchase CT radiographic units and in cooperation with the State Racing Board to require horses that had a history of significant “lay up timemust have negative CT scans prior to a return to racing.

      The large number of publications from this study resulted in more than 20 invitations to present our gross, radiographic, and histopathologic findings and interpretation of the pathogenesis of those lesions at local, national, and international meetings and several awards and in honors for our group efforts.

       My most appreciated honor from the Horseracing Industry was a letter from Mr. John E. Anthony, Loblolly Farms, Lake Hamilton, Arkansas for my having provided a second opinion report regarding the necropsy re his horse, Prairie Bayou, that he raised, trained, and owned. This 3yr-old, TB won the Preakness Stakes, was 2nd in the Kentucky Derby and shattered a cannon bone in the Belmont Stakes. Necropsy findings published in the New York Times indicated, without supporting histologic evidence, that Prairie Bayous’ catastrophic limb failure occurred secondary to corticosteroid injections in ligaments of that limb causing limb failure.

      I was contacted by Mr. Anthony who asked me to review the radiographs and necropsy findings. I interpreted the radiographs, reviewed the histopathology findings, and found no evidence to support the original diagnosis. The radiographic findings were identical to many similar catastrophic limb failures of young, 3–5-year-old TB racehorses that were in my CAHRB Breakdown Study caused by mechanical injury. Many were demonstrated as being secondary to stress fractures. After contacting Mr. Anthony with my findings, I shared my findings with a colleague who was also experienced with pathologic findings in limb injuries in athlete horses and he agreed with my findings and conclusions. With the permission of Mr. Anthony, we published our findings. Pool R.R. and C.W. McIlwraith. Necropsy of Prairie Bayou: A Look at the Facts. The Equine Athlete (Mar-Apr): 1995.

       Fracture patterns result from predictable applied mechanical forces. Fracture healing mechanisms are complicated and require an understanding of (1) the role played by a focal loss of oxygen tension due to a localized disruption of the local blood supply at the fracture site, (2) resulting hypoxia that activates MSCs and vessels in the periosteum to form the external callus and (3) MSCs and vessels in the fatty marrow and endosteal lining adjacent to the inner cortical surface at the fracture line that form the internal callus, (4) the role of CBRUs in bridging the fracture line by insertion of osteons and (5) role of mechanical stability, i.e., an orthopedic appliance, that allows a stable union. Terminology often used to describe fracture healing is: Primary healing, i.e., osteonal bridging and Secondary healing, i.e., by callus formation to stabilize the fracture line that permits repair and remodeling of the fracture line.

      Fracture patterns in long bones result from mechanical forces acting on structural elements of a bone. Bone tissue is formed primarily of mineral (e.g., hydroxyapatite) and only a relatively small fraction of Type 1 collagen that provides the tensile strength of bone. Therefore, a long bone behaves mechanically like a homogenesis brittle substance– i.e., like a piece of chalk.

1- Fracture patterns generated by predictable forces

      Complete transverse fracture: When one attempts to snap a piece of chalk in half using your thumb to press in the middle or compression side of the piece of chalk while simultaneously creating tension on the side opposite the thumb when pulling the ends toward the thumb, a complete transverse fracture occurs. The fracture line begins on the tension side of the chalk that is opposite the thumb and exits on the chalk surface at the site of compression by the thumb.

       Short oblique fracture: Place fingers of both hands at either end of a piece of chalk. While holding and pushing, i.e., compressing, the ends of the chalk towards its middle, slowly twist (torsion) each end in opposite directions until the middle of the chalk fails and forms a short oblique (torsion) fracture.

      Long oblique or spiral fracture: Place fingers of both hands at each end of a piece of chalk. While holding and pulling the ends away from the center exerts tension. Slowly twist (torsion) each end of the piece of chalk in opposite directions until the middle develops a long oblique or spiral (tension) fracture.

      Compression fracture: Place a vertically oriented piece of chalk on a hard flat surface and hit it with a hammer. The piece of chalk fractures and shatters into multiple fracture fragments having no repeatable patterns. This is the feature of a compression fracture of a homogeneous brittle substance.

2- Repair of cortical bone fractures by Primary Union, i.e., osteonal reconstruction.

      Nondisplaced stable complete transverse cortical fracture of a long bone while placed under sustained compression by an orthopedic appliance: When a complete transverse fracture line in the midshaft region of a long bone is placed under compression by an orthopedic appliance, the compression of the fracture line exceeds local vascular perfusion pressures causing focal ischemia at that site. Resulting low oxygen tension presumably triggers viable vessels in adjacent Volkmann canals on either side of the fracture line to give rise to CBRUs. Cutting cones then invaded and pass through the fracture line while filling cones form osteons that bridge the fracture line in a process called direct bone healing.

      Recall that the central region of the surface of a long bone is not covered by a layer of soft tissue and muscle, e.g., the cannon bone of a horse. Here, there is centrifugal (outward bound) blood flow through the cortex of the diaphysis. At this location the blood flow originates from a branch of the diaphyseal nutrient artery in medullary cavity. Blood from the medullary cavity flows via vessels in Volkmann canals through the cortical bone to emerge on the cortical surface where it leaves by periosteal veins.

      Nondisplaced complete transverse cortical fracture of a long bone having a narrow gap between aligned ends of cortical fracture surfaces while placed under sustained compression by an orthopedic appliance: After (1) ischemia has activated MSCs in periosteum and/or endosteum to (2) fill the narrow fracture gap with woven bone or after an osteogenic implant has filled the gap and (3) after he fracture line has been placed under compression by an orthopedic appliance, compression of the fracture line (4) increases focal ischemia.  Low oxygen tension at that site presumably triggers viable vessels in adjacent Volkmann canals to give rise to (5) CBRUs. Cutting cones then invade and pass through the mineralized bone in the former gap in the fracture line and enter the opposing cortical bone surface followed by the filling cones that form osteons which bridge the fracture line.

3- Repair of cortical bone fractures by Secondary Union from Callus Formation.

    Displacement of a complete thickness fracture line of the shaft of a long bone causes (disruption of the periosteum, and its blood supply while elevating the overlying soft tissues and skin. Trauma creates a focal area of ischemia, edema, and hemorrhage in which hypoxia activates resting MSCs and recruits vessels in the superficial tissues.  Together, MSCs and newly recruited vessels during the next few days participate in the formation of an external callus.

      Simultaneous disruption of the endosteal surface of the cortex causes separation of the attached endosteal lining, fibrous stroma containing fatty marrow and capillary bed causing hemorrhage. Trauma lowers the already normal low oxygen tension of this affected area in the medullary cavity. Location of the fracture line in the diaphysis of a cannon bone relative to the location of the diaphyseal nutrient artery and its possible disruption may be important factors that delay the healing process.

      External callus formation relies on the MSCs, and a new vascular supply recruited from the overlying soft tissue. However, the cortical surface of some bones, e.g., midshaft MCIII of the horse, has relatively little soft tissue on that surface. Absence of soft tissue structures may result in delayed fracture healing as compared to other fracture sites having overlying muscles, tendons, tendon sheaths and abundant subcutaneous adipose tissue all of which have a rich blood supply and MSCs that they can share with the repair process. Fractures in young animals heal faster because of greater vascularity and associated MSCs than healing that occurs in bones that are fractured in older animals.

      Both the external and internal callus formation follow sequential replacement of the initially disrupted soft tissues that have been partially separated from the cortical bone surface at the emergence of the fracture line where a hematoma has formed. The hematoma creates a focal area of low oxygen tension that activates a reparative response from MSCs and recruits new vascular ingrowth. Together, they replace the hematoma with osteogenic granulation tissue. The reparative response that organizes replacement of the periosteal hematoma also extends into and organizes the hematoma in the medullary cavity. In the medullary cavity it forms a temporary plug of woven bone. However, by the end of the fracture healing process, the medullary plug will be removed by bone remodeling units since following fracture repair, that plug serves no mechanical or other functional purpose.

      At time of fracture occurrence there is tearing and separation of the focal attachments of the periosteum and endosteum to their respective borders on either side of the fracture line. Disruption provokes stem cells in those structures to begin the formation of bridges of woven bone that during the healing process will form an external and an internal callus of cancellous bone.  In time the reparative response will form bridges of cancellous bone that cross and stabilize the fracture line allowing bone remodeling units to unite the opposing ends of fracture surfaces of cortical bone.     

4- Effects of mechanical forces on repair during callus formation, i.e., secondary union:

(1) Instability affects external and external callus formation by decreasing their blood flow. Movement compresses and compromises blood flow at the fracture site causing a lowering of  oxygen tension in environment where periosteal and endosteal repair occurs. In this environment of hypoxia and movement, the recruited MSCs form cartilage rather than bone matrix.  

      For example, prior to the fracture occurrence, an osteogenic layer of the periosteum was present on the cortical bone surface of the animal. However, fracture causes immediate instability of the cortical surface. This results in vascular disruption and hemorrhage that creates ischemia and lowers oxygen tension in the soft tissue of the bone surface. Movement and lower oxygen tension combined to cause the MSCs in the periosteum to undergo transformation and revert to the earlier fetal state of formation of a chondrogenic layer of the periosteum. Therefore, MSC repair cells are stimulated and begin to form a chondrogenic periosteal response which, in turn, produces a less stable external callus that results in a delayed union fracture.

(2) MSCs located in the external and internal callus of a healing fracture line that undergoes tension will form fibrous tissue, i.e., fibrous union, or result in a delayed union.

(3) Fracture healing may be complicated by movement, poor alignment, fracture gaps filled with soft tissue including muscle and infection resulting in pseudoarthrosis (false joints).

Understanding of the origin of stem cells and their roles in repair and neoplastic transformation to form a spectrum of benign to malignant tumors clarifies the classification system of tumors of the musculoskeletal system. The following discussion primarily concerns mesenchymal stems cells of mesodermal origin, esp. bones and joints.

Brief review. Developmental embryology and tissue formation potential of embryonic cells.

Potential: < Totipotent >                      <Pluripotent>                        <Multipotent>

Origin:      Zygote> Morula>             Blastula> Gastrula>                 Organogenesis

Zygote is a fertilized egg, and it can form an entire body.

Morula is a solid ball of 8-16 cells created by cell divisions of a fertilized egg.

Blastula is hollow ball of ~100 cells each called blastomeres having a hollow center or


Gastrula arises from a blastula that develops by an enfolding of a blastopore at the future proctodeum. i.e., future rear end of the animal!!  Enfolded blastopore forms a cylindrical tube that advances through the center of this elongated ovoid structure until the end of the tube opens onto the surface of the opposite end where it forms the stomodeum, i.e., future oral cavity.

      Ectoderm: Cells lining the outermost layer of the gastrula form the ectoderm that gives rise to the skin and its related structures.

      Mesoderm: This cellular layer lies between the superficial ectodermal layer and the centrally located cylindrical tube of endoderm. The mesoderm gives rise to subcutaneous tissue, connective tissue, skeletal muscle and the skeletal system of bones and joints.

      Endoderm: This central cylindrical tube gives rise to the gut and adjacent derived structures.

Significance: Developmental cells from each of the three developmental layers and their accompaniment of “resting” stem cells in each of the three layers can only form structures and tissues that are developmentally limited to their specific layer. In each layer a few cells remain as resting reserve cells, i.e., stem cells, with each one having multipotential capacity.  However, “resting” MSCs when activated are also limited to form tissues/structures characteristic only of their respective layer. MSCs remain in postnatal life to function in repair of damage in tissues of that layer. Stem cells in skin should not be able to form bone, etc. Stem cells are said to rest in “niches”.

      However, in rare situations, stem cells in one layer can dedifferentiate, e.g. I recently examined a tumor in connective tissue having features of a carcinosarcoma but that is the exception.

This presentation only concerns stem cells of mesodermal origin, called mesenchymal stem cells (MSCs) which have multipotential capacity to form bone, cartilage, fibrous and adipose tissue and that can be activated by low oxygen tension, i.e., hypoxia. When they undergo neoplastic transformation, they become self-renewing tumor cells capable of forming benign or malignant tumors that form one or more of the four tissue types.

      Benign and Low-grade Malignant Multipotential Tumors of Mesoderm arising in:

1. Facia connecting and supporting the surfaces of skeletal muscle, tendons, and ligaments

2. Fibrous tissue attachment to periosteal surfaces of bone

3. Fibrous periosteum

4. Superficial layer of the osteogenic layer of the periosteum

5. Mid to deep regions of the osteogenic layer of the periosteum

1. Facia and connective tissue that supports and lines surfaces of skeletal muscle, tendons, and ligaments:

      Resting MSCs are present in all the fibrous tissue structural elements of the musculoskeletal system including the epimysium of skeletal muscles, epitenon of tendons and epiligamentum of ligaments. MSCs in all these locations when activated by hypoxia following injury can initiate repair or may undergo neoplastic change to form benign or malignant tumors of cartilage, bone, fibrous or adipose tissue.

      The myosatellite cells are MSCs that rest on the basement membrane of the plasmalemma of a skeletal muscle fiber. They participate in the repair of a damaged skeletal muscle fiber. When activated, they pass through the plasmalemma of the skeletal muscle fiber into its sarcolemma tube. There the MSCs differentiate into myoblasts that proliferate and form a central cellular chain before fusing with one another and initiate myofibrillar genesis. Their synthetic activity restores the contractile elements in the sarcoplasm of the muscle fiber. Afterwards, they differentiate into myocytes. MSCS also participate in muscle fiber hypertrophy. MSCs are likely involved in the formation of rhabdomyoma and rhabdomyosarcoma. 

      MSCs are present in the connective tissue investments of tendons include the epitenon that covers loose fibrous tissue of the mesotenon, which in turn, attaches to the endotenon of the fascicles of longitudinally oriented, primary tendon bundles and that accompany longitudinally oriented vessels in tendon, e.g., DDF tendon of a horse. MSCs are present as resting repair cells in these structures.

      During my examination of necropsy tissues collected from horses in the CHRB Racetrack Breakdown Project, there was an ample opportunity to find and sample focal linear degenerative lesions in tendons and ligaments. These sites exhibited histologic evidence of ischemic damage and attempts at spontaneous repair. Here bundles of collagen fascicles had collapsed due to ischemic damage. There was a loss of viable fibrocytes and viable vasculature. In many specimens, spontaneous repair had been initiated by the infiltration of new longitudinally oriented vessels that extended into the mass of degenerative collagen bundles. Pericytes emerged from the outer wall of the new arteries where they proliferated and formed an encircling mass of fibroblasts. In time this layer of fibroblasts formed a new elongated linear fascicle of newly formed collagen fibers encasing a tiny central artery. The result was a newly formed bundle or collagen fascicle that had a small artery in its center. Therefore, a new pattern of vessels orientation replaced the normal pattern of longitudinal fascicles separated by longitudinally oriented vessels. However, these newly formed fascicles were composed of weaker Type III collagen rather than normal stronger Type I collagen in tendon or ligament fascicles.

     Illustrations listed below are present in my Equine Musculoskeletal Pathology Library.

Examples include Para-ligamental chondromas observed in horses were most likely benign tumors that arose from traumatically activated MSCs in the fatty fibrous tissue that attaches to the suspensory ligament of a horse; Para-tendon chondromas in the DDFT tendon in digit -5 in a 9yr Labret; Para-ligamental chondroma in the LF lateral branch of the suspensory ligament in 5yr., TB; Para-ligamental chondroma in the LF medial branch of the suspensory ligament in 16yr. Paso.

2. Nodular cartilaginous lesions caused by activation of “resting” MSCs by an abrasion of the surface of articular cartilage and in injured synovial linings of joints:

      MSCs are activated by trauma (ischemia) to the repair of an abraded joint surface. Activated MSCs in the subintimal layer of the articular cartilage when partially torn from the joint surface can form cartilage nodules. MSCs in the injured subintimal lining of the synovial membrane lining a joint can also form similar cartilage nodules or chondromas.

      Recent investigations have indicated that MSCs located in the synovial lining may include MSCs having two biologically different properties. Synovial MSCs identified as SMSCs may include two different categories of differentiation and clinical behavior, i.e., Primary (PSC) and Secondary (SPC) osteochondromas.  

Secondary (SPCs) nodules are formed as a reactive response to trauma to the synovium and lack FGFR3, a spontaneous biological product that when formed stimulates cartilage proliferation, i.e., traumatic lesions of the synovial surface. They form small cartilage nodules.

Primary (SPCs) arise from MSCs embedded in the synovial lining. While most of these SPC-derived osteochondromas have diploid cells and exhibit benign features, some embedded SPCs derived osteochondromas are not diploid and are positive for PCNA and FGFR3 that promote proliferation. These may produce multiple nodules that recur following removal, i.e., synovial osteochondromatosis.

      Examples below of osteochondromas are included in my Stem Cell Library: Nodular lesion from outer margin of the articular cartilage of proximal femur of a dog; Secondary synovial osteochondromas in hip joint of a QH and in the patellar synovium of a TB horse; Primary multicentric synovial osteochondromatosis in a DSH cat and in an older dog; Primary bilateral synovial osteochondromatosis in the proximal humerus of a cat; Multicentric viral osteochondromatosis in a 4 yr.-old cat; Para-articular chondromas and osteochondromatosis in facia attaching to the fibrous layer of the joint capsule of the elbow of 7yr. Gershep; Hock of a 9yr Labret; Hock 7yr, Mxdbd dog; Hock 12yr, TB horse; dist. MT4

3. Benign and Low-grade Malignant Tumors of Bone Surfaces Arising from MSCs Include:

            Fascial connective tissue attachments to fibrous periosteum of a bone

            Fibrous periosteum

            Outer layer of the osteogenic layer of the periosteum

            Middle to deep layer of the osteogenic layer of the periosteum

Example of gross, radiographic, and histologic images of most of the following in my Stem Cell Library:

            Juvenile ossifying fibroma in a young horse

            Periosteal fibrosarcoma in a cat

            Maxillary fibrosarcoma of periosteal origin in dogs

            Periosteal chondroma in a dog and a horse

            Periosteal intermediate-grade chondrosarcoma in a dog

            Periosteal compact and cancellous osteomas in cats

            Parosteal osteosarcomas in 2 dogs and 1 cat.

            Parosteal osteosarcoma with lung metastases in a dog

            Parosteal (multifocal) ossifying lipomas in a cat.

            Fascial ossifying lipoma arising in the neck region of a dog.

            Periosteal low-grade osteosarcoma in a dog (WHO Surface Osteosarcoma

 4. Malignant Bone Tumors of the Deeper Osteogenic Layers of the Periosteum and Medullary Cavity that Arise from Neoplastic Transformation in MSCs


Osteosarcoma and its subtypes:

            Poorly differentiated

            Osteoblastic: Nonproductive and Productive




            Giant cell type




Giant cell tumor of bone

Multilobular tumor of bone (arises in suture lines)

Example of gross, radiographic, and histologic images of most of the following in my Stem Cell Library:

            Osteoblastoma in a distal humerus in a dog and a cat

            Poorly differentiated osteosarcoma in a dog

            Nonproductive osteosarcoma in a dog

            Productive osteosarcoma in a dog

            Osteoblastic osteosarcoma in humerus, ischium, proximal tibia in 3 dogs

            Chondroblastic osteosarcoma in a dog

            Low-grade fibroblastic osteosarcoma in a dog

            High-grade fibroblastic osteosarcoma in a dog

            Telangiectatic osteosarcoma in a dog

            Giant Cell variant osteosarcoma in a dog

            Chondrosarcoma of a rib in a dog     

            Central chondrosarcoma of femur and humerus in 2 dogs    

            Chondrosarcoma of vertical ramus of mandible in a dog

            Central hemangiosarcoma of distal femur in a dog

            Giant cell tumor in d. ulna, d. humerus, prox. radius in 3 dogs

            Multilobular tumor of the skull in 4 dogs

I decided to pursue another adventure and retire from UCD SVM in 1994. This was due to a change in school and departmental administration. For 25 years I had enjoyed working with clinical comrades as we delivered an organ-based teaching curriculum that involved the collaborative participation of faculty in several interrelated clinical disciplines.  We taught together, participated in diagnosis of hospital patients, and engaged in collaborative research together. The new program would be a return to a traditional departmentally oriented teaching program that I recall was boring.

      During my career at UCD SVM I authored or co-authored 124 publications in professional and scientific journals, 35 publications of findings in DOE sponsored Ra226/Sr90 lifespan study involving in beagles in Radiation Research Journals; and 30 publications of several professional organizations including the thoroughbred racing industry, animal breeders and zoos.  

      Adventure as a musculoskeletal pathologist for a national commercial veterinary pathology company (IDEXX) was a most enjoyable professional experience since many of the submissions were orthopedic specimens and bone tumors that would not have been routinely submitted to the VMTH of a veterinary school. This experience allowed me to examine large numbers of orthopedic lesions and musculoskeletal tumors mostly of small animals and exotic pets as well as oral/dental lesions and tumors. However, I was easily recruited back into academia since I missed instruction of veterinary students.

      Adventure at Cornell University College of Veterinary Medicine began with an academic appointment in which I had teaching, diagnostic and research roles like those at UCD SVM. While Cornell had a departmentally oriented curriculum, I found a friendly acceptance by my new colleagues and enjoyed collaborative teaching, service, and research interactions across all clinical departments. Once again, racing thoroughbred horses were patients that infrequently came to necropsy. While I was enjoying my professional adventure at Cornell, I was contacted by the assistant dean of research at Mississippi State College of Veterinary Medicine. He invited me to be the bone pathologist for a well-financed research project whose mission was to develop an intra-articular anti-inflammatory therapeutic for racehorses and other athletic horses. I received permission from the dean and my department head at Cornell to be absent from Friday noon until Monday noon a few times each month at which times I was not scheduled for teaching or necropsy duty. In time the research project progressively required more time. I reluctantly left Cornell for another adventure at Miss State that offered a tenure track appointment as professor and a laboratory with orthopedic equipment necessary to complete the research mission.

      Adventure at Mississippi State College of Veterinary Medicine began in 2000. The project to develop an intra-articular, injectable anti-inflammatory medication was sponsored by Luitpold Pharmaceuticals. Research used beagles to create a synovitis model whose inflammatory effect could be controlled by a new anti-inflammatory drug.  We already knew that synovitis was caused by articular surface abrasion in fetlock joints of racing and athletic horses. The experimental model used beagle dogs. The anterior cruciate ligament of the stifle joint was transected. The resulting joint instability created abnormal friction between opposing joint surfaces. Products from joint surface abrasion then elicits inflammation, i.e., synovitis. Protocols determined the dates when the joints from euthanized dogs were to be sampled for examination and interpretation. Tissues for examination were removed from opposing joint surfaces and synovium in both operated control dogs and operated dogs that received anti-inflammatory medication. Tissue specimen identifications from control and treated dogs were blinded for histological examination. The project was successful in bringing Adequan to market. Adequan remains in current use. Awards were received because of the nationally recognized importance of this product. Our research resulted in several invited presentations at professional meetings.

      A new dean at Miss State arrived just prior to my appointment. After he had reviewed the current veterinary curriculum, he decided to make changes. When he learned that I had been a committee member of “Current Analysis of Veterinary Pathology”, a national program for instructional development, NIH, Department of Health Education and Welfare, he invited me work with him and faculty committees of the school to implement changes in the curriculum. However, after 3 enjoyable academic years at Miss State, I missed working with orthopedic problems of racing thoroughbreds and other athletic horses. Consequently, I was easily recruited by the pathology faculty at Texas A&M University, School of Veterinary Medicine, and Biomedical Sciences after they informed me that 25% of the horses in this country live in Texas and about 10% are lame.

      Adventure at TAMU SVMBS began in 2003 with an appointment as a clinical professor.

During my 15-year appointment at TAMU SVMBS I continued to teach a musculoskeletal pathology course that attempted to integrate and explain how histopathologic mechanisms provoked by different causes alter normal bone structure in certain unique patterns that are manifest in diagnostic radiographic images.

      My laboratory specimens included a unique collection of dried bone specimens with their accompanying clinical radiograph and history for 55 orthopedic and bone tumors specimens from dogs and cats and 43 orthopedic and bone tumor specimens from horses and cattle. I had previously used these specimens in my UCD SVM laboratory presentation, which at that earlier time in my career, had received the Norden Teaching Award.      

        After I initially participated as a faculty member in the biopsy and necropsy service, I was appointed Director of the Pathology Service in 2006. For these efforts I received a clinical service award in 2013.  I also opened Osteopathology and Dental Pathology Services to recruit case submissions from private practices. I actively participated in the necropsy service until my appointment terminated in 2018. However, I was permitted to continue to have access to my faculty office.

     From 2003 until the termination of my appointment in 2018, I had 54 publications as author or co-author and delivered 63 invited presentations at state, regional, national, and international professional and scientific meetings.

      Research with colleagues during and after retirement involved the use of stem cells to facilitate healing in articular cartilage and tendons. Two unique publications reported the role-played by stem cells from male fetal lambs in healing complete thickness trephine defects placed in the major weight-bearing articular surface of the medial femoral condyle of adult female ewes. Male fetal stem cells while remaining at the periphery of the defect, promoted otherwise inactive female host stem cells of the ewe to repair the articular defect.  (Sheep embryonic stem-like cells transplanted in full-thickness cartilage defects. J. of Tissue Engineering and Regenerative Medicine 2009; 3(3): 175-187)

      Following retirement, I have continued to collect and accept donations of orthopedic specimens and bone tumors for my Teaching Archive. I have continued to work without monetary compensation while aiding veterinarians at other veterinary colleges in this country and abroad who sought my interpretation of changes in their bone specimens and asked for copies of my specimen illustrations, lectures, and seminars for instructional purposes.

      Since retirement I have made presentations for the ANTECH Imaging Retreat in Jackson, WY., and TAMU Feline Forum.

      Retirement has allowed time for 28 co-authored publications. Two of the more significant publications include:

1.  Neoplastic transformation of arteriopathy-derived bone infarct into a nascent osteosarcoma in the proximal tibia in a miniature schnauzer. Case Report Vet Record 2022:10.e293

2. Canine idiopathic arteriopathy, appendicular bone infarcts, and neoplastic transformation of bone infarcts in 108 dogs. Comparative Medicine, 2022.DOI: 10.30802/AALAS-CM-22-000037

This study involving 653 dogs explains that although the locations and biological behavior of bone tumors are similar in both man and dogs, an idiopathic arteriopathy causing infarcts in dogs is responsible for dogs to having 27 times more bone tumors than in man.

      Retirement has also allowed time to complete Four Illustrated Instructional Libraries that are free and are easily downloaded from the internet:

1.  Bone library also includes dental pathology

2.  Stem cell library includes embryological origin, MSC location in tissues, their roles in repair, their cause of tumors, locations in limbs and types of tumors arising in those locations.

3.  Feline bone tumors and how stem cells may form different histologic patterns in same location

4.  Equine: head including airway. jaws, dental arcade, developmental, nutritional/metabolic, 

spine, limbs, navicular disease, laminitis, tendons, and ligaments


     In January 2024 I received an email from Dr. Francisco Uzal, Chief Executive Officer, Davis-Thompson Foundation. “…. we are sharing the links to a large amount of exceptional teaching material on musculoskeletal pathology of multiple animal species, generously shared by Dr. Roy Pool, Texas A&M. This is a gold mine for trainees and pathologists interested in musculoskeletal pathology; enjoy!

     Recently I received an e-mail from Dr. Lisa Fortier, Editor of JAMA, who notified me that the Journal of the American Veterinary Medical Association is promoting my four instructional libraries in a soon to be released edition of that journal. 

       Veterinary Record Case Reports sent me an e-mail with the following message:

            “Congratulations on being recognized as a top-downloaded author in Veterinary Record Case Reports.”

Roy R Pool, DVM PhD

Emeritus Prof. Vet Pathology UCD SVM 1994

Clinical Prof. Emeritus Vet Pathobiology TAMU SVMBS 2018


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Rafaela De Negri

Rafaela De Negri


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