Collagenase 3 production by human osteoarthritic chondrocytes in response to growth factors and cytokines is a function of the physiologic state of the cells

Objective. We investigated the response of human osteoarthritic (OA) chondr ocytes, in terms of collagenase 3 production, to growth factors and cytokin es involved in the anabolism and catabolism of articular cartilage, and exp lored the major signaling pathways leading to its up-regulation. Methods. Human OA chondrocytes were treated with the following factors: the proinflammatory cytokine interleukin-1 beta (IL-1 beta), the growth factor s basic fibroblast growth factor (bFGF), platelet-derived growth factor BE (PDGF-BB), parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), transforming growth factor beta 1 (TGF beta 1), and TGF beta 2, the protei n kinase (PK) activator antagonists for PKC, PKA, and PKG pathways, and pho spholipase A(2) and tyrosine kinases, as well as the antiinflammatory cytok ines IL-4, IL-10, and IL-13. Collagenase 3 expression and synthesis were de termined. Comparison was made with collagenase 1. Results. The human OA chondrocyte population could be divided into 2 catego ries: the L chondrocytes, showing low collagenase 3 basal synthesis levels and high sensitivity to IL-1 beta stimulation; and the H chondrocytes, high collagenase 3 basal synthesis levels and low IL-1 beta inducibility. In L chondrocytes, all growth factors stimulated collagenase 3 production. In H chondrocytes, PTH, IGF-1, and TGF beta had little or no impact; bFGF slight ly stimulated it and PDGF-BB showed the same pattern as in the L chondrocyt es. The effects of all growth factors, except TGF beta, on collagenase 1 sy nthesis followed those of collagenase 3, albeit to a higher degree. Interes tingly and unlike collagenase 3, the effects of TGF beta on collagenase 1 c ould not be related to the state of the cells, but rather, depended on the isoform. Indeed, TGF beta 2 did not induce collagenase 1 synthesis, whereas TGF beta 1 stimulated it. Among the PK activators tested, phorbol myristat e acetate was the strongest inducer, suggesting a major involvement of the PKC pathway. IL-13 inhibited collagenase 3 production, IL-4 had little effe ct, and IL-10 had none. Conclusion. This study shows that collagenase 3 production in human OA chon drocytes depends on the physiologic state of the cell. TGF beta might be re sponsible for the change in cells from the L to the H state. Importantly, o ur in vitro data implicate TGF beta 2 as a possible in vivo agent capable o f specifically triggering collagenase 3 production over that of collagenase 1 in OA cartilage.