Chondroitin Sulfate Promotes Activation of Cathepsin K [Protein Synthesis and Degradation]

June 23rd, 2014 by Lemaire, P. A., Huang, L., Zhuo, Y., Lu, J., Bahnck, C., Stachel, S. J., Carroll, S. S., Duong, L. T.

Cathepsin K (CatK), a major lysosomal collagenase produced by osteoclasts, plays an important role in bone resorption. Evidence exists that the collagenase activity of CatK is promoted by chondroitin sulfate (CS), a sulfated glycosaminoglycan. This study examines the role of CS in facilitating CatK activation. We have demonstrated that chondroitin 4-sulfate (C4-S) promotes auto-processing of the pro-domain of CatK at pH 5 leading to a fully matured enzyme with collagenase and peptidase activities. We present evidence to demonstrate this auto-activation process is a trans activation event that is efficiently inhibited by both the covalent cysteine protease inhibitor E-64 and the reversible selective CatK inhibitor L-006,235. During bone resorption, CatK and C4-S are co-localized at the ruffled border between osteoclast bone interface, supporting the proposal that CatK activation is accomplished through the combined action of the acidic environment together with the presence of a high concentration of C4-S. Formation of a multimeric complex between C4-S and pro-CatK has been speculated to accelerate CatK auto-activation and promote efficient collagen degradation. Together, these results demonstrate CS plays an important role in contributing to the enhanced efficiency of CatK collagenase activity in vivo.