Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions.

OBJECTIVE: To relate the rate of bone resorption to serum levels of both hyaluronan (HA) and antigenic keratan sulfate (KS) in canine experimental osteoarthritis (OA) and to evaluate the effects of calcitonin on these parameters and the OA lesions of the unstable knee. METHODS: Twenty-two dogs underwent anterior cruciate ligament transection (ACLT) and 6 dogs underwent sham operation. Urinary pyridinium crosslinks were quantified by high-performance liquid chromatography. Immunoassays quantified hyaluronan (HA) and antigenic KS. Macroscopic and histologic OA lesions were scored. Calcitonin treatment was started on day 14 postsurgery and stopped on either day 49 or day 104 postsurgery. Control dogs and all treated dogs were killed on day 105. RESULTS: All ACLT joints developed OA. In contrast to sham-operated animals, all operated dogs exhibited an early and sustained rise in the levels of their urinary and serum markers. Calcitonin markedly reduced the levels of these markers and the severity of OA lesions. Furthermore, the longer the period of calcitonin therapy, the lower the score of the OA lesions. CONCLUSION: Bone, synovium, and articular cartilage all appear to be involved in the state of hypermetabolism that develops in unstable joints. Furthermore, the rate of bone resorption increases markedly in the early stages of this OA model and is likely to contribute to cartilage breakdown. Since calcitonin reduced the severity of OA changes, this form of therapy may have benefits for humans who have recently experienced a traumatic knee injury.

Characterization of crosslinked collagens synthesized by mature articular chondrocytes cultured in alginate beads: comparison of two distinct matrix compartments.

We have characterized immunohistochemically and biochemically the collagens accumulating in two compartments of the matrix formed by mature bovine articular chondrocytes in alginate beads. At all times of the 28-day culture period, more than 90% of the collagen molecules were recovered from the rim of cell-associated matrix (CM) which encapsulates individual chondrocytes and chondrocyte clusters. Both the total amount and concentration of collagens in this matrix compartment rose progressively with time. The ratio of collagen/proteoglycan remained relatively constant with time and was always five to seven times higher in the CM than in the interterritorial matrix compartment further removed from the cells. In the CM, collagen types II, IX and XI were present on Day 28 in relative proportions (95/l/3) similar to those in adult cartilage. A higher proportion of newly synthesized collagen type XI than types II or IX molecules did not become incorporated into the pericellular rim of matrix but accumulated in the further removed matrix. Although collagen type I was synthesized in small amounts by flattened cells at the surface of the beads, it did not become incorporated as heterotrimers or homotrimers in the matrix. Mature pyridinium crosslinks, principally pyridinoline, were detected as early as Day 7 of culture but became much more abundant between Days 15 and 28, especially in the CM which contained at all times more than 90% of the crosslinks formed. The codistribution of collagen types II, IX and XI and mature collagen-specific crosslinks support the contention that mature chondrocytes cultured in alginate matrix surround themselves with a protective shell whose composition is very similar to that which encapsulated the cells in vivo.

Elevation in urinary levels of pyridinium cross-links of collagen following chymopapain-induced degradation of articular cartilage in the rabbit knee provides evidence of metabolic changes in bone.

To measure urinary levels of two pyridinium cross-links of collagens at various times, rabbits were injected in the left knee with 0.2 mg (N = 11) or 2.0 mg chymopapain (N = 11). Urinary levels of the bone-specific deoxy-pyridinoline cross-link and of the hydroxylysyl pyridinoline cross-link, found in large amounts in articular cartilage and bone, were measured by high performance liquid chromatography (HPLC). The urinary levels were correlated with histological evidence of progressive articular cartilage destruction in animals injected with 2.0 mg chymopapain and of successful repair in rabbits injected with the lower dose. Rabbits injected with 2.0 mg chymopapain showed a very large increase in urinary levels of deoxy-pyridinoline during the first 30 days after the injection. This rise was not seen in animals injected with the lower dose. A rise in urinary level of the hydroxylysyl pyridonline cross-link was observed in all rabbits but was more pronounced and lasted longer in animals receiving the higher dose. The failure of rabbits injected with 2.0 mg chymopapain to repair the damaged articular cartilage was strongly associated with a marked increase in the catabolism of the bone-specific deoxy-pyridinoline cross-link and to a lesser extent with the catabolism of the hydroxylysyl pyridinoline found in bone and in articular cartilage.