Cathy S. Carlson

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.

Occult osteochondral lesions (bone bruises) have been documented on magnetic resonance images in more than 80% of patients sustaining acute anterior cruciate ligament ruptures. Despite the high prevalence of these lesions, little is known about the histologic changes in the adjacent articular cartilage. Ten patients with acute anterior cruciate ligament ruptures who had a preoperatively documented (by magnetic resonance imaging) geographic bone bruise at the sulcus terminalis on the lateral femoral condyle underwent a 3-mm diameter trephine biopsy of the articular cartilage and subchondral bone overlying the bone bruise at the time of anterior cruciate ligament reconstruction. Biopsy samples of the articular cartilage and subchondral bone were stained with hematoxylin and eosin and toluidine blue. All patients had significant arthroscopic and histologic articular cartilage irregularity in the area overlying the bone bruise. Arthroscopic findings of the articular cartilage included softening (dimpling), fissuring, or overt chondral fracture. Histologic examination revealed degeneration of the chondrocytes and loss of toluidine blue staining in the articular cartilage (loss of proteoglycan). There was necrosis of osteocytes in the subchondral bone, and empty lacuna were visible. This study defines the exact histologic changes of the articular cartilage overlying a geographic bone bruise secondary to an acute anterior cruciate ligament tear. Our findings suggest that a geographic bone bruise found on magnetic resonance imaging indicates substantial damage to normal articular cartilage homeostasis.

OBJECTIVE: The receptor for advanced glycation end products (RAGE) binds multiple ligands, including S100 proteins, high mobility group box chromosomal protein 1 (HMGB-1), and AGEs, all of which are present in articular cartilage. Stimulation of RAGE signaling can lead to MAP kinase activation and increased NF-kappaB activity. The objective of the present study was to determine if chondrocytes express functional RAGE. METHODS: The presence of chondrocyte RAGE was analyzed by immunohistochemistry using normal and osteoarthritic (OA) cartilage from young and old monkeys and humans, immunoblotting of chondrocyte lysates and human cartilage extracts, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of RNA from chondrocytes treated with interleukin-1 (IL-1) and fibronectin fragments. RAGE signaling was evaluated by stimulating chondrocytes with S100B and HMGB-1 and analyzing for activation of the ERK MAP kinase and NF-kappaB. The ability of S100B and HMGB-1 to stimulate matrix metalloproteinase 13 (MMP-13) production was also assessed. A pull-down assay using biotin-labeled S100B was used to demonstrate binding to RAGE. RESULTS: RAGE was detected in sections of monkey knee cartilage and human knee and ankle cartilage. Increased immunostaining for RAGE was noted in cartilage from older adult monkeys and humans and was further increased in OA tissue. RAGE was also detected by immunoblotting and by RT-PCR, where IL-1beta and fibronectin fragments were found to stimulate RAGE expression. Stimulation of chondrocytes with S100B or HMGB-1 increased phosphorylation of the ERK MAP kinase and the p65 subunit of NF-kappaB and increased the production of MMP-13. This signaling was inhibited in cells pretreated with soluble RAGE, and S100B was shown to bind to chondrocyte RAGE. CONCLUSION: Articular chondrocytes express functional RAGE. The increase in RAGE noted in OA cartilage and the ability of RAGE ligands to stimulate chondrocyte MAP kinase and NF-kappaB activity and to stimulate MMP-13 production suggests that chondrocyte RAGE signaling could play a role in OA.

OBJECTIVE: To determine whether oxidative damage to cartilage proteins can be detected in aging and osteoarthritic (OA) cartilage, and to correlate the results with the local production of interleukin-1beta (IL-1beta) and the responsiveness of isolated chondrocytes to stimulation with insulin-like growth factor 1 (IGF-1). METHODS: The presence of nitrotyrosine was used as a measure of oxidative damage. Histologic sections of knee articular cartilage, obtained from young adult and old adult cynomolgus monkeys, which develop age-related, naturally occurring OA, were evaluated. Each cartilage section was graded histologically on a scale of 0-7 for the presence of OA-like changes, and serial sections were immunostained using antibodies to nitrotyrosine and IL-1beta. Chondrocytes isolated and cultured from cartilage adjacent to the sections used for immunostaining were tested for their response to IGF-1 stimulation by measuring sulfate incorporation in alginate cultures. For comparison with the monkey tissues, cartilage sections from human tissue donors and from tissue removed at the time of OA-related joint replacement surgery were also immunostained for nitrotyrosine and IL-1beta. RESULTS: The presence of nitrotyrosine was associated with aging and with the development of OA in cartilage samples from both monkeys and humans. All sections that were highly positive for IL-1beta also showed staining for nitrotyrosine. However, in a few sections from older adult monkeys and humans, nitrotyrosine was present but IL-1beta was absent, suggesting that some age-related oxidative damage is independent of IL-1beta. In chondrocytes that were isolated from monkey cartilage positive for nitrotyrosine or IL-1beta, the response to stimulation with IGF-1 was significantly reduced. In some samples from older adult monkeys, IGF-1 resistance was seen in cells isolated from tissue that did not stain for nitrotyrosine or IL-1beta. CONCLUSION: Oxidative damage due to the concomitant overproduction of nitric oxide and other reactive oxygen species is present in both aging and OA cartilage. This damage can contribute to the resistance of chondrocytes to IGF-1 stimulation, but it is unlikely to be the sole cause of IGF-1 resistance in these chondrocytes.