Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin K

Abstract

Objective. Several recent studies have demonstrated that cathepsin K, a proteolytic enzyme capable of degrading native fibrillar collagen, is overexpressed in osteoarthritic cartilage and inflamed synovial tissue. However, it is not known whether increased cathepsin K production is a primary or a secondary event in these diseases. The availability of transgenic UTU17 mice, which exhibit constitutive overexpression of the cathepsin K gene, prompted us to study possible arthritic changes in their knee joints.Methods. Progression of synovitis and articular cartilage degeneration in the knee joints of UTU17 mice and their nontransgenic littermates was monitored by histologic analyses at 7 and 12 months of age. Distribution of cathepsin K in the knee joints was studied by immunohistochemistry.Results. At the age of 7 months, UTU17 mice exhibited clear signs of synovitis, with strong immunostaining for cathepsin K in the synovial lining and the stroma, while control knee joints appeared normal. At 12 months, marked synovial thickening and fibrosis and severe degradation of cartilage and subchondral bone were observed in UTU17 mouse knee joints. In areas of cartilage degeneration, both chondrocytes and cells of hypertrophic synovia were positive for cathepsin K. At 12 months, synovia of control mice revealed only a few isolated cathepsin K-positive cells and mild changes in articular cartilage.Conclusion. Our findings demonstrate that overexpression of the cathepsin K gene under its own promoter in transgenic mice makes them susceptible to progressive synovitis, which, upon aging, results in synovial hyperplasia and fibrosis and subsequent destruction of articular cartilage and bone.

Joint Destruction and Osteoporosis are Associated with Upregulation of IL34 and Cathepsin k Expression in Rheumatoid Arthritis. Clinical Trial with Anti TNF α Therapy

“…Morko et al, mentioned that overexpression of cathepsin K leads to spontaneous synovitis and cartilage erosion in RA [51].…”

Effects of PTH [1-34] on synoviopathy in an experimental model of osteoarthritis preceded by osteoporosis

“…In fact, chronic synovial pathology has been detected after OA induction by meniscectomy in an ovine model 17 . In addition, intra articular injections of transforming growth factor (TGF)-b induced synovial hyperplasia and osteophyte formation in a mouse model 18 , and a transgenic mouse model overexpressing cathepsin K spontaneously developed synovitis 19 . We have recently demonstrated that PTH reduced knee-cartilage damage mainly by improving subchondral bone quality in a rabbit model of combined OA and osteoporosis (OP) 20 .…”

Cysteine Cathepsins and the Skeleton

“…In a dog osteoarthritis model, a potent inhibitor of cathepsin K (SB-55348) decreased the overall tibial degeneration score by 21% and the cartilage degradation score by 32% [105]. In contrast, overexpression of cathepsin K in mice showed increased cathepsin K expression in chondrocytes and led to the spontaneous development of synovitis and cartilage degradation [98,106]. However, the role of cathepsin K in arthritic diseases is not undisputed.…”