Inhibition of insulin‐like growth factor binding protein 5 proteolysis in articular cartilage and joint fluid results in enhanced concentrations of insulin‐like growth factor 1 and is associated with improved osteoarthritis

Objective The complement component C1s is present in dog joint fluid in an activated state. Since C1s degrades insulin‐like growth factor binding protein 5 (IGFBP‐5), we undertook to determine whether inhibiting C1s in joint fluid would result in an increase in the amount of intact IGFBP‐5 and IGF‐1 in cartilage and joint fluid, and whether C1s inhibition would be associated with a reduction in cartilage destruction during the development of osteoarthritis (OA). Methods Twenty‐two dogs were randomized to 3 treatment groups. All dogs underwent anterior cruciate ligament transection and were exercised. Dogs received 1 of 3 treatments: buffer alone (controls; n = 6); PB‐145, a peptide derived from the sequence of antithrombin III (n = 9); and pentosan polysulfate (PPS; n = 7). PB‐145 or saline was injected into the joint space 3 times per week for 3 weeks. PPS was injected intramuscularly weekly for 3 weeks. Results Joint histology showed preservation of chondrocytes and a smooth joint surface in the animals treated with PB‐145 and PPS. Mankin scoring showed statistically significant reductions in joint destruction with PB‐145 and PPS treatments (P < 0.01) compared with buffer control. Mean active collagenase concentrations were decreased by these two treatments. Immunoblotting of joint fluid showed that both treatments increased concentrations of intact IGFBP‐5. Direct analysis of IGFBP‐3 and IGFBP‐5 protease activity showed that IGFBP‐5 was degraded more rapidly and that PB‐145 and PPS inhibited the degradation of both proteins. Total IGF‐1 concentrations in joint fluid were increased 5.6–5.8‐fold by these two treatments. Analysis showed that C1s was being activated in joint fluid and that its activation was inhibited by the addition of PB‐145 or PPS. Conclusion The findings suggest that direct inhibition of the serine protease C1s results in increased concentrations of intact IGFBP‐5 and that proteolysis of IGFBP‐3 is also inhibited, probably by the inhibition of some other protease. This increase in concentrations of intact IGFBP‐3 and IGFBP‐5 leads to an increase in IGF‐1 which is associated with an improvement in joint architecture during the development of OA.