Pathogenesis Of Osteochondrosis Research Articles

Angular limb deformity associated with TSPAN18, NRG3 and NOVA2 in Rambouillet rams

Angular limb deformity (ALD) affects many species of livestock and companion animals. The mechanisms of ALD development are not well understood, but previous research suggests the involvement of genetic risk factors. A case-control genome-wide association study (GWAS) was conducted with 40 ALD-affected and 302 unaffected Rambouillet rams and 40,945 single nucleotide polymorphisms (SNPs). Forelimbs of 6 ALD-affected rams were examined and diagnosed with osteochondrosis. Genome-wide or chromosome-wide significant SNPs were positioned exonic, intronic or within the 3′UTR of genes TSPAN18, NRG3 and NOVA2, respectively. These genes have previously described roles related to angiogenesis and osteoblast, osteoclast and chondrocyte proliferation and differentiation, which suggests the possibility for their involvement in the pathogenesis of osteochondrosis. Functional consequences of SNPs were evaluated through transcription factor binding site analysis, which predicted binding sites for transcription factors of known importance to bone growth, including SOX6, SOX9 and RUNX2. The identification of genetic risk factors for ALD may help to improve animal welfare and production in Rambouillet, a breed known to be at risk for ALD development. This study proposes genes TSPAN18, NRG3 and NOVA2 as targets for further research towards understanding the etiology of ALD in Rambouillet sheep.

Comparative label-free proteomic analysis of equine osteochondrotic chondrocytes

Osteochondrosis is a developmental orthopedic disease affecting growing cartilage in young horses. In this study we compared the proteomes of equine chondrocytes obtained from healthy and osteochondrotic cartilage using a label-free mass spectrometry approach. Quantitative changes of some proteins selected for their involvement in different functional pathways highlighted by the bioinformatics analysis, were validated by western blotting, while biochemical alterations of extracellular matrix were confirmed via Raman spectroscopy analysis. In total 1637 proteins were identified, of which 59 were differentially abundant. Overall, the results highlighted differentially represented proteins involved in metabolic and functional pathways that may be related to the failure of the endochondral ossification process occurring in osteochondrosis. In particular, we identified proteins involved in extracellular matrix degradation and organization, vitamin metabolism, osteoblast differentiation, apoptosis, protein folding and localization, signalling and gene expression modulation and lysosomal activities. These results provide valuable new insights to elucidate the underlying molecular mechanisms associated with the development and progression of osteochondrosis. SignificanceOsteochondrosis is a common articular disorder in young horses mainly due to defects in endochondral ossification. The pathogenesis of osteochondrosis is still poorly understood and only a limited number of proteomic studies have been conducted. This study provides a comprehensive characterization of proteomic alterations occurring in equine osteochondrotic chondrocytes, the only resident cell type that modulates differentiation and maturation of articular cartilage. The results evidenced alterations in abundance of proteins involved in functional and metabolic pathways and in extracellular matrix remodelling. These findings could help clarify some molecular aspects of osteochondrosis and open new fields of research for elucidating the pathogenesis of this disease.

Changes in Bone Density in Patients with Osteochondrosis of the Cervical Spine

Osteoporosis and osteochondrosis have common clinical manifestations: poor posture, reduced flexibility and mobility of the spine, joint pain, fatigue, weakness; both diseases appear most often in old age. Having a lot in common in symptoms, osteoporosis and osteochondrosis differ in etiology, treatment and prognosis. The development of osteoporosis is based on impaired bone remodeling, but it has been established that this process is also important in the pathogenesis of osteochondrosis. The results of previous studies indicate that there is a relationship between the functional state of the neuromotor apparatus and the violation of the structure of bone tissue in the spinal canal stenosis of the lumbar spine. There is data on the study of the nerve conduction and bone mineral density in patients with osteochondrosis of the cervical spine in a small sample. To study the functional state of peripheral nerves and the presence of disorders of bone tissue structure in 2018, 25 patients of the neurosurgical department of Irkutsk Scientific Centre of Surgery and Traumatology were observed with the diagnosis "Dorsopathy, Osteochondrosis of the cervical spine" (М50.1) and 25 volunteers of the control group, representative of the main sex and age. As a result of the examination, all patients of the main group showed sufficiently deep afferent-efferent dysfunctions of the segment apparatus of the cervical spine, while in the control group changes in ENMG indicators showing initial changes in the function of the neuromotor apparatus were observed in 20 % of the examined. The change in bone density was observed in most of the main group examined (72 %), in the control group the decrease in bone density was less frequent (54 %, of which 29 % registered osteopenia). The results of the examination indicate the existence of a relationship between osteochondrosis and osteoporosis - the more symptoms of sensory-motor dysfunction of the root increase in osteochondrosis of the cervical spine, the more often the change in bone density - osteoporosis or osteopenia - is diagnosed.

Imaging of osteochondrosis.

Osteochondrosis is an abnormality of the epiphyses or epiphyseal equivalents (round bones and apophyses) during later stages of endochondral ossification. This process of abnormal endochondral ossification can occur at various locations throughout the body. The pathogenesis of osteochondrosis is under active investigation. In humans, the process of abnormal endochondral ossification has been attributed to a combination of vascular insult and trauma. Although the proposed etiology of osteochondrosis varies based on body part affected, the overall process is defined by necrosis, revascularization and repair. As such, common radiologic findings include those of osseous destruction and associated inflammation. The purpose of this review is to discuss the current understanding of osteochondroses as a disease entity and explore imaging features of osteochondroses throughout the body.

Disarticulation-Associated Femoral Head Separation in Clinically Normal Broilers: Histologic Documentation of Underlying and Predisposing Cartilage Abnormalities.

Routine and quantitative histologic studies on femoral head separation (FHS) associated with coxofemoral joint disarticulation at necropsy were conducted on 125 femoral heads collected from 21- to 50-day-old clinically normal broilers. The study compared groups demonstrating grossly detached femoral heads (DFHs) with those having attached femoral heads (AFHs). Marked microscopic lesions compatible with osteochondrosis (OCD) consistently occurred along the separation surface in the DFH population. The histologic changes consisted of cartilage degeneration and necrosis sometimes forming small clefts or microfractures. Hemorrhage and less frequent inflammatory cells were often present along the separation surfaces. Small foci of OCD in the femur occurred in the AFH group with lesser frequency and severity. The histologic changes were mainly found within the proximal proliferative zone of the physis near the epiphyseal junction. Histomorphometry disclosed significant quantitative reductions in chondrocyte density with increased pyknosis occurring adjacent to the separation site and to a lesser extent in deeper regions of the growth plate for the DFH compared with AFH. Measurements made along the separation surface of the percentage length occupied by osteochondrotic defects and actual separated cartilage disclosed significant differences between evaluation groups. However, determinations of vascular canal areas present within two or more regions of the growth plate revealed a slight and significant increased area for DFH compared with AFH. Severity scores for the occurrence of microthrombi within the growth plate showed no difference between the groups. The pathogenesis of FHS in broilers is related to defective cartilage production or degeneration resulting in increased fragility. This contrasts with the proposed pathogenesis of OCD in mammals, which involves ischemic necrosis due to underlying vascular defects. The results for the FHS-disarticulation model also differ from those reported for glucorticoid-induced femoral head necrosis in broilers. The FHS-associated lesions occurred without histologic evidence of bacterial chondritis or osteomyelitis.

Osteochondrosis in the Distal Femoral Physis of Pigs Starts With Vascular Failure.

Articular osteochondrosis (OC) arises due to vascular failure and ischemic chondronecrosis. The aim of the study was to describe the histological and computed tomographic (CT) characteristics of changes in the distal femoral physis of pigs, to determine if they represented OC lesions and if the pathogenesis was the same as for articular OC. The material included 19 male Landrace pigs bred for predisposition to OC. One or 2 pigs were euthanized and CT-scanned at 2-week intervals from 82 to 180 days of age. Material from 10 pigs was available for histological validation. The CT scans revealed 31 lesions confirmed in 3 planes and 1 additional macroscopically visible lesion confirmed in 2 CT planes. Twelve of the lesions were histologically validated. All lesions were compatible with OC. Cartilage canal and eosinophilic streak morphological changes corresponded to failure of end arteries coursing from the epiphysis, toward the metaphysis. The location of lesions was compatible with failure at the point of vessel incorporation into bone. Vascular failure was associated with retention of viable hypertrophic chondrocytes and delayed ossification but not cartilage necrosis. Lesion width ranged from 1.1% to 45.6% of the physis. Several lesions were expected to resolve due to small size and evidence of CT-identifiable, reparative ossification. Angular limb deformity was not detected in any pig. The pathogenesis of physeal OC started with vascular failure that was morphologically identical to articular OC. The heritable predisposition may therefore be the same. The association between lesions and limb deformity should be studied further in older pigs in future.

The Pathogenesis of Osteochondrosis in Humans and Animals

Osteochondrosis is a disease involving failure of endochondral ossification that occurs in growing animals and children in highly specific predilection sites, resulting in the formation of a cartilaginous or osseocartilaginous flap that causes pain and locking of the joint. In veterinary medicine, the term “osteochondrosis” (OC) is used for all stages of the disease and all affected sites. In human medicine, “osteochondritis dissecans” (OCD), is the preferred term for clinical disease involving the distal femur/knee joint. In other affected sites in humans, the disease is named after the physician(s) who first recognized it at that site; the disease in humans is further subdivided into adult and juvenile forms. Until very recently, subclinical disease was not recognized in humans as the only available tissue for study was the flap removed surgically from the affected joint, which often had been present for months to years. Subclinical disease, however, is well recognized in animals due to study of predilection sites at ages prior to the age of onset of clinical disease, work that are not possible in humans. Because the appearances of the subclinical and clinical disease are completely different, and because only end‐state tissue has been available for study of the disease in humans, the pathogenesis of the disease has been poorly understood in human medicine. In pigs and horses, it has been well demonstrated that subclinical lesions of osteochondrosis involving the articular‐epiphyseal cartilage complex are composed of areas of necrotic epiphyseal cartilage that often surround necrotic cartilage canal blood vessels. The overlying articular cartilage and subjacent subchondral bone are not initially affected; however, as endochondral ossification proceeds these areas of necrotic cartilage cause a delay in the ossification front that is visible in imaging studies. Study of both naturally‐occurring and surgically‐induced disease in animals have unequivocally demonstrated that failure of cartilage canal blood supply is the cause of these lesions. Traumatic forces to the surface of the articular cartilage, even when minimal in severity, may result in collapse of the necrotic epiphyseal cartilage and cleft formation through the overlying articular cartilage, resulting in the well‐recognized clinical disease. Recent development of magnetic resonance imaging methods to identify cartilage canal vessels and areas of cartilage necrosis, as well as access to human cadaveric knee specimens, have provided strong evidence that the pathogenesis of OC/OCD in animals and humans is identical and that subclinical disease in humans occurs years before clinical disease is evident. This work provides the potential for the development of new methods of early detection of disease in humans and methods for monitoring its response to treatment.Support or Funding InformationNIH/NIAMS R01AR070020; NIH/OD K01OD021293; WM Keck FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

An Update on the Pathogenesis of Osteochondrosis.

Osteochondrosis is defined as a focal disturbance in endochondral ossification. The cartilage superficial to an osteochondrosis lesion can fracture, giving rise to fragments in joints known as osteochondrosis dissecans (OCD). In pigs and horses, it has been confirmed that the disturbance in ossification is the result of failure of the blood supply to epiphyseal growth cartilage and associated ischemic chondronecrosis. The earliest lesion following vascular failure is an area of ischemic chondronecrosis at an intermediate depth of the growth cartilage (osteochondrosis latens) that is detectable ex vivo, indirectly using contrast-enhanced micro- and conventional computed tomography (CT) or directly using adiabatic T1ρ magnetic resonance imaging. More chronic lesions of ischemic chondronecrosis within the ossification front (osteochondrosis manifesta) are detectable by the same techniques and have also been followed longitudinally in pigs using plain CT. The results confirm that lesions sometimes undergo spontaneous resolution, and in combination, CT and histology observations indicate that this occurs by filling of radiolucent defects with bone from separate centers of endochondral ossification that form superficial to lesions and by phagocytosis and intramembranous ossification of granulation tissue that forms deep to lesions. Research is currently aimed at discovering the cause of the vascular failure in osteochondrosis, and studies of spontaneous lesions suggest that failure is associated with the process of incorporating blood vessels into the advancing ossification front during growth. Experimental studies also show that bacteremia can lead to vascular occlusion. Future challenges are to differentiate between causes of vascular failure and to discover the nature of the heritable predisposition for osteochondrosis.

Problems and pointers in osteochondrosis: Twenty years on

Twenty years ago a supplement of Equine Veterinary Journal was devoted to equine osteochondrosis (OC) and recognised the importance of this developmental disease to the equine industry. In the accompanying editorial several controversial issues were identified and a number of areas for further research were highlighted. Today, equine OC is still a major clinical problem, but the on-going research has resulted in much improved knowledge and understanding of this highly complicated disease.There is still conflicting evidence on the prevalence of OC due to the dynamic character of the condition, widely varying definitions in the literature, and the range of joints affected. Nevertheless there is now convincing evidence that early vascular damage, leading to chondronecrosis, is the major mechanism of onset. The aetiological factors that determine whether a horse will develop clinical signs of OC remain obscure and the complex nature of OC and its multi-factorial character has been clearly demonstrated by genetic studies. These have shown a multitude of loci on a variety of chromosomes linked to osteochondrotic phenotypes, depending on the type of manifestation of OC, the joint involved and the breed. The controversy surrounding the possible key role of copper in the pathogenesis of OC in the early 1990s has evolved into a more limited contribution to repair thus making it just one of the many environmental factors that may have an effect on the occurrence of OC, but not a decisive one.The semantic debate concerning the most appropriate nomenclature seems to have crystallised into a consensus on terminology at three levels: OC or osteochondritis dissecans (OCD) for the disturbance in the process of endochondral ossification, juvenile ostechondral conditions (JOCC) for all joint and growth plate related disorders, and developmental orthopaedic diseases (DOD) for the full range of skeletal conditions in young horses. Future progress in improved management of OC can be expected from more research on cellular and molecular processes and the influences that determine the process of endochondral ossification, the process of articular cartilage maturation, and from epidemiological studies quantifying the long-term effects of OC on health and performance.

Heritability estimates of tarsocrural osteochondrosis and palmar/plantar first phalanx osteochondral fragments inStandardbred trotters

The pathogenesis of osteochondrosis (OC) and palmar/plantar first phalanx osteochondral fragments (POFs) is multifactorial, but specific knowledge of heritability is limited. To improve the precision of heritability estimates and to estimate the genetic correlation between tarsocrural OC and POFs in Standardbred trotters. Further aims were to examine whether the prevalence of OC/POFs was different in the American and French lineages that have contributed to the Norwegian population, and if the prevalence was affected by heterozygosity. Retrospective cohort study. Categorical data on tarsocrural OC and POFs from 2 radiographic studies performed in 1989 and 2007/2008 (n = 1217) were analysed with sire threshold models that included 230 sires. Heritability of OC at the distal intermediate ridge of the tibia and/or the lateral trochlear ridge of the talus was estimated at 0.29 ± 0.15. For OC at the distal intermediate ridge of the tibia only, the estimate was 0.40 ± 0.17. Heritability of POFs in all 4 limbs was estimated at 0.23 ± 0.13; for metatarsophalangeal POFs this was 0.26 ± 0.13 and for medial metatarsophalangeal POFs 0.32 ± 0.14. Estimates of genetic correlation between OC and POFs ranged from 0.68 ± 0.27 to 0.73 ± 0.28 but were not significantly different from a zero-genetic correlation. Effects of lineages or heterozygosity were not observed. This study confirmed a moderate to high heritability of tarsocrural OC and POF, providing further evidence of the heritable nature of these diseases. Examination of specific lesions yielded the highest heritability; therefore, breeding programmes and future genome-analysis studies should focus on predilection sites rather than the entire disease complex.

Transection of vessels in epiphyseal cartilage canals leads to osteochondrosis and osteochondrosis dissecans in the femoro-patellar joint of foals; a potential model of juvenile osteochondritis dissecans

To transect blood vessels within epiphyseal cartilage canals and observe whether this resulted in ischaemic chondronecrosis, an associated focal delay in enchondral ossification [osteochondrosis (OC)] and pathological cartilage fracture [osteochondrosis dissecans (OCD)] in the distal femur of foals, with potential translational value to the pathogenesis of juvenile osteochondritis dissecans (JOCD) in children. Ten Norwegian Fjord Pony foals were operated at the age of 13-15 days. Two vessels supplying the epiphyseal growth cartilage of the lateral trochlear ridge of the left distal femur were transected in each foal. Follow-up examination was carried out from 1 to 49 days post-operatively and included plain radiography, macroscopic and histological examination. Transection of blood vessels within epiphyseal cartilage canals resulted in necrosis of vessels and chondrocytes, i.e., ischaemic chondronecrosis, in foals. Areas of ischaemic chondronecrosis were associated with a focal delay in enchondral ossification (OC) in foals examined 21 days or more after transection, and pathological cartilage fracture (OCD) in one foal examined 42 days after transection. The ischaemic hypothesis for the pathogenesis of OC has been reproduced experimentally in foals. There are several similarities between OCD in animals and JOCD in children. It should be investigated whether JOCD also occurs due to a focal failure in the cartilage canal blood supply, followed by ischaemic chondronecrosis.

Molecular characterization and methylation study of matrix gla protein in articular cartilage from pig with osteochondrosis

Osteochondrosis (OC) or leg weakness is an economically important disease of young fast growing pigs and is a concern of animal welfare. The etiology and pathogenesis of osteochondrosis is not fully understood yet, but any abnormalities in the formation of hypertrophic chondrocytes and disrupted blood supply to the growth cartilage are very important predisposing factors. Matrix gla protein (MGP) as a potential calcification inhibitor of extracellular matrix might contribute to the development of OC. Molecular characterization, polymorphisms analysis, methylation at promoter region and expression of MGP gene and protein were performed in both healthy and OC cartilage collected from a Duroc × Pietrain resource population. The porcine MGP gene consists of 4 exons and 3 introns. The full-length MGP cDNA isolated from articular cartilage consists of 606 bp with a 69-bp 5′ UTR, a 312-bp open reading frame with a start codon, a 225-bp 3′ UTR. Three single-nucleotide polymorphisms (SNP) were detected in the intron 1 (A-115G, C-1073T and C-1135A) and one in the 3′UTR (C-3767T). The relative abundance of MGP mRNA was lower ( P < 0.05) in OC compared with healthy cartilage. Moreover, the intensity of MGP band was lower ( P < 0.05) in OC group when quantified by western blot. Furthermore, one CpG region was identified in MGP promoter and DNA methylation of three CG sites were higher in OC compared with normal cartilage. This suggested that the high DNA methylation at specific CG sites in the MGP promoter might be involved in the down regulation of MGP in OC. Immunofluorescence of normal cartilage collected from pigs of different ages revealed that MGP signals were higher in younger pigs and decreased in the older pigs. The MGP protein was expressed more near to the cartilage canals. These results suggest that the MGP gene might be a potential candidate gene for the development of OC in pigs.

The Candidate Gene XIRP2 at a Quantitative Gene Locus on Equine Chromosome 18 Associated with Osteochondrosis in Fetlock and Hock Joints of South German Coldblood Horses

A whole-genome scan for radiological signs of osteochondrosis (OC) and osteochondrosis dissecans (OCD) in South German Coldblood (SGC) horses using 250 microsatellite markers identified a genome-wide significant quantitative trait locus (QTL) for fetlock OCD and a chromosome-wide QTL for hock OC on Equus caballus chromosome (ECA) 18 at a relative position of 45.9-78.2 cM. The aim of this study was to analyze associations of single-nucleotide polymorphisms (SNPs) in candidate genes for OC in this QTL region using 96 SGC horses. The OC-QTL on ECA18 could be confirmed and narrowed down to an interval of 13 Mb between GALNT13 and Xin actin-binding repeat containing 2 (XIRP2). SNPs in the XIRP2 gene were significantly associated with fetlock OC, fetlock OCD, and hock OC. The significant associations of SNPs in XIRP2 could be confirmed in linear animal models controlling for systematic environmental and residual quantitative genetic effects. The significant additive genetic effects of the intronic SNPs (AJ885515:g.159A>G, AJ885515:g.445T>C) in XIRP2 were 0.15 (P = 0.01) for fetlock OC, 0.27 (P = 0.01) for fetlock OCD, and 0.15-0.16 (P = 0.01-0.02) for hock OC. Homozygous (A/A or T/T) and heterozygous horses were at a 1.3- to 2.4-fold higher risk for fetlock and hock OC. These results suggest that dominant variants of XIRP2 may be involved in pathogenesis of equine OC.

Epiphyseal cartilage canal blood supply to the tarsus of foals and relationship to osteochondrosis

Pathological changes in the blood supply to growth cartilage have been implicated in the pathogenesis of osteochondrosis (OC) in horses, but have not been reported using vascular perfusion techniques. To describe the developmental pattern of cartilage canal vessels in the distal tibial epiphysis and talar growth cartilage of foals. Nine foals bred from parents with OC were sacrificed between the ages of 0 and 7 weeks to undergo a barium perfusion procedure. The distal end of the tibia and the entire talus were cleared in methyl salicylate and perfused vessels studied in the intact bones. Slabs with a thickness of 4-5 mm from 3 predilection sites for OC were examined in the stereomicroscope and with light microscopy. Cartilage canals were present for a limited period of growth. Perfused vessels initially entered canals from the perichondrium. Vessels in the proximal portion of canals retained their perichondrial arterial source throughout. With time, the ossification front advanced to incorporate the mid-portion of canals; and anastomoses formed between canal vessels and subchondral vessels. A shift occurred and vessels in the distal terminus of canals came to use subchondral vessels as their arterial source. Twelve histological lesions were found in 7 foals. All contained necrotic vessels surrounded by necrotic growth cartilage and 3 caused macroscopically visible delay in endochondral ossification. Lesions were located where vessels traversed the ossification front to enter the distal terminus of canals. Cartilage canal vessels are particularly susceptible to failure at the point where they cross the ossification front, with consequences for the viability of those chondrocytes that depend on them. A better understanding of how lesions of OC arise may improve the ability to identify, monitor, prevent and treat this disorder. Involvement of cartilage canals in the pathogenesis of equine tarsal OC plausibly explains several clinical features of this disease.

Etiology and Pathogenesis of Osteochondrosis

Osteochondrosis is a common and clinically important joint disorder that occurs in human beings and in multiple animal species, most commonly pigs, horses, and dogs. This disorder is defined as a focal disturbance of enchondral ossification and is regarded as having a multifactorial etiology, with no single factor accounting for all aspects of the disease. The most commonly cited etiologic factors are heredity, rapid growth, anatomic conformation, trauma, and dietary imbalances; however, only heredity and anatomic conformation are well supported by the scientific literature. The way in which the disease is initiated has been debated. Although formation of a fragile cartilage, failure of chondrocyte differentiation, subchondral bone necrosis, and failure of blood supply to the growth cartilage all have been proposed as the initial step in the pathogenesis, the recent literature strongly supports failure of blood supply to growth cartilage as being the most likely. The term osteochondrosis has been used to describe a wide range of different lesions among different species. We suggest a refinement of this terminology to include the modifiers latens (lesion confined to epiphyseal cartilage), manifesta (lesion accompanied by delay in endochondral ossification), and dissecans (cleft formation through articular cartilage). The purpose of this review is to provide an overview of the disease, focusing on the most commonly cited theories, recent research findings, and our own views regarding the etiology and pathogenesis of osteochondrosis, in order to provide a better understanding of this apparently complex disease.

Early lesions of osteochondrosis in the distal tibia of foals

Material available for research into osteochondrosis (OC) in humans tends to represent chronic lesions. Comparative studies of early lesions in young animals are, therefore, important in clarifying the pathogenesis of OC in humans. Recent studies in pigs provide strong evidence that lesions of articular OC are associated with a focal failure in the cartilage canal vascular supply to epiphyseal growth cartilage (articular-epiphyseal cartilage complex excluding the articular cartilage). The purpose of the present study was to examine histological sections from a specific predilection site for articular OC in the distal tibia of a large number of young foals to determine if the same is true in horses. Material from the distal tibiae of 100 foals aged from 191 days of gestation to 153 days old was collected from routine submissions of fetuses and foals for post mortem examination. The tibiae were band-sawed into slabs, and selected slabs were processed for histology, stained with hematoxylin and eosin, and examined using light microscopy. Early subclinical developmental stages of OC were found in the most common site for clinical OC lesions of horses in nine of 100 foals aged 12 to 122 days old. All lesions contained areas of chondrocyte necrosis that were associated with cartilage canal necrosis in five of nine foals. Five of these foals also had focal disruption of enchondral ossification at the chondro-osseous junction in the same site. Early lesions purported to play a role in the initial stages of articular OC in the distal tibia of horses were characterized by chondrocyte necrosis and likely occurred secondary to a failure of cartilage canal vascular supply to epiphyseal growth cartilage. The similarities in appearance between early lesions of piglets and foals suggest that information gained in one species may be transferable to others, including humans.

The Cartilage Canals of the Epiphyseal Growth Cartilage and their Role in the Formation of Lesions of Osteochondrosis

Cartilage canals are temporary vascular structures within the growth cartilage. They were described as early as 1736 and the first perfusion study performed already in 1743. In its most complex form, the vascular structure consists of an arteriole, originating in the perichondrial plexus and branching out into an anastomosing network of capillaries. The capillaries circle back along the arteriole and rejoin into a venule that follows the course of the arteriole back to the plexus. The canals regress with age in a process designated as chondrification, where the content of the canals is replaced by cartilage. The process of chondrification is considered physiological; however, premature regression has been associated with the formation of lesions of osteochondrosis. The purpose of the present study was to gain further insight into the nature of chondrification and the initial steps in the pathogenesis of osteochondrosis and the relationship between these events and age, growth rate, weight and femoral shape of the individual animals. This involved studies of the distribution and pattern of regression of the cartilage canals. The articular‐epiphyseal cartilage complexes of the distal femur of 48 half‐siblings of the Norwegian Landrace pig breed were studied, combining techniques of perfusion and tissue clearing with histological and immunohistological methods. The results of this study indicate that the physiological regression of the cartilage canals is an orderly and time‐dependent process in which the endothelial cells at the termination of the vessels die by apoptosis, while perivascular cells differentiate into chondrocytes that fill in the cartilage canal with matrix. However, as the ossification front advances, the deepest portion of some of the canals form anastomoses with vessels of the subchondral bone, giving the axial portion of the growth cartilage a new source of blood supply. Lesions of osteochondrosis, typically occurring in the axial growth cartilage, are characterized by necrosis of the portion of the affected cartilage canal distal to a point of interruption, with subsequent necrosis of adjacent resting zone growth cartilage. This interruption occurs at the junction between cartilage and bone where anastomoses are formed between cartilage canal vessels and subchondral vessels.

Characterizing osteochondrosis in the dog: potential roles for matrix metalloproteinases and mechanical load in pathogenesis and disease progression

To address possible roles of matrix metalloproteinases (MMPs) and mechanical stress in the pathogenesis of osteochondrosis (OC). Naturally-occurring canine OC lesions (n=50) were immunohistochemically analyzed for MMP-1, -3, and -13, and normal canine articular cartilage explants (n=6) cultured under 0-, 2-, or 4-MPa compressive loads (0.1 Hz, 20 min every 8 h up to 12 days) were compared to OC samples (n=4) biochemically and molecularly. MMP-1 and -3 immunoreactivities were readily detected in both OC samples and control tissues obtained from age-matched dogs (n=11) whereas MMP-13 was only detectable in OC samples. MMP-13 gene expression as determined by real-time reverse transcription polymerase chain reaction was elevated in OC samples and cartilage explants cultured without mechanical stimuli (0 MPa groups) compared to normal cartilage (day 0 controls). Glycosaminoglycan content (per weight) in cartilage explants cultured under no load was significantly (P<0.05) lower on day 12 than in the day 0 controls. Gene expression levels of aggrecan and type II collagen in OC samples were lower than those in the day 0 controls. High levels of aggrecan and collagen II expression were seen in the 2 MPa groups. These findings imply that impaired biochemical characteristics in OC-affected cartilage may be attributable to decreased extracellular matrix production that may stem from disruption of normal weight bearing forces.

Focal changes in blood supply during normal epiphyseal growth are central in the pathogenesis of osteochondrosis in pigs

Cartilage canals are temporary vessel-containing structures within the growth cartilage. The canals gradually regress with age in a process designated chondrification, where the content of the canals is replaced by cartilage. The process of chondrification is considered physiological; however, premature regression has been associated with the formation of lesions of osteochondrosis. The purpose of the present study was to gain further insight into the nature of and relationship between chondrification of cartilage canals and the initial steps in the pathogenesis of osteochondrosis with respect to morphology, presence of factors influencing the processes, and mode of cellular death. The articular–epiphyseal cartilage complexes of the distal femur of 48 pigs were studied, combining a technique of perfusion and tissue clearing with histological and immunohistological methods. The results provided strong evidence that the process of chondrification occurs at the terminations of the cartilage canals and is characterized by disintegration of the endothelial cells and transformation of perivascular cells into matrix-producing chondrocytes. Lesions of osteochondrosis, however, are characterized by necrosis of the portion of the affected cartilage canal distal to a point of interruption, with subsequent necrosis of adjacent resting zone growth cartilage. This interruption of the cartilage canal blood supply occurs at the junction between cartilage and bone where anastomoses are formed between cartilage canal vessels and vessels from the bone marrow. It is possible that microfractures occurring secondary to minor trauma at a vulnerable time in the development of the cartilage may be the initial event in pathogenesis of osteochondrosis.

Excessive degradation of type II collagen in articular cartilage in equine osteochondrosis

Articular osteochondrosis (OCD) occurs in both man and animals. The etiology remains to be determined. Studies of OCD lesions in animals may provide clues as to its pathogenesis. The aim of our study was to determine whether there was evidence for increased degradation namely proteoglycan (PG) release and type II collagen cleavage in articular cartilage harvested from OCD lesions. We examined ex vivo explants at post-mortem from equine OCD lesions and macroscopically normal site and age matched cartilage. These were cultured over a 10 day period in serum-free medium. Type II collagen cleavage was measured in articular cartilage and media using an Elisa assay to detect the COL2-3/4C short epitope, which is generated on cleavage of the triple helix of type II collagen by collagenases. PG release was measured by a dye-binding assay. Cumulative release of PG and COL2-3/4C short and their contents in cartilage at the end of the culture period were determined. In OCD lesions there was a significant increase in type II collagen cleavage by collagenase but no evidence for increase of PG degradation. These findings point to a selective increase in type II collagen cleavage by collagenases, in OCD lesions of the kind observed in osteoarthritis. Further work is needed to determine whether changes represent primary or secondary events in the pathogenesis of OCD.