The regulation of cathepsin K gene expression.

Cathepsin K is essential for normal bone resorption. Osteoclasts synthesize and secrete cathepsin Kinto the extracellular compartment at the attachment site between osteoclasts and the bone surface, wherein the organic matrix is subsequently degraded by cathepsin K. RANKL, NFAT, Mitf, and various components of AP-1 enhance osteoclast formation and bone resorption, whereas IFN-gamma, calcitonin, estradiol, and calcium inhibit it. These agents appear to act correspondingly to alter cathepsin K mRNA and protein expression in order to stimulate and suppress the osteoclast's resorbing potential. RANKL signaling via the calcineurin-calcium-NFAT signaling cascade plays a significant role in the regulation of cathepsin K expression. Activation via p38 and the micropthalmia transcription factor also enhances cathepsin K expression. Future studies will be needed to elucidate the relative roles of various signaling pathways at different stages of osteoclast formation and activation and to determine whether genetically disrupting these pathways can modulate bone resorption with or without impeding other osteoclast functions.