title: Chondroitin sulfate promotes activation of cathepsin K.
abstract: 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 autoprocessing 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 autoactivation 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 autoactivation and promote efficient collagen degradation. Together, these results demonstrate that CS plays an important role in contributing to the enhanced efficiency of CatK collagenase activity in vivo.
authors: From the Departments of In Vitro Pharmacology.
authors: Peter A
authors: PA
authors: Lemaire
authors: Bone Biology.
authors: Lingyi
authors: L
authors: Huang
authors: Bone Biology.
authors: Ya
authors: Y
authors: Zhuo
authors: Structural Chemistry, and.
authors: Jun
authors: J
authors: Lu
authors: From the Departments of In Vitro Pharmacology.
authors: Carolyn
authors: C
authors: Bahnck
authors: Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors: Shawn J
authors: SJ
authors: Stachel
authors: From the Departments of In Vitro Pharmacology.
authors: Steve S
authors: SS
authors: Carroll
authors: Bone Biology, le_duong@merck.com.
authors: Le T
authors: LT
authors: Duong
mesh_terms: D056657:Cathepsin K / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D011499:Protein Processing, Post-Translational
chemical_list: D002809:Chondroitin Sulfates; D056657:Cathepsin K
keywords: Activation; Bone; Cathepsin K; Chondroitin Sulfate; Collagenase; Osteoarthritis; Osteoclast; Osteocyte; Osteoporosis; Peptidase,