Structural basis of collagen fiber degradation by cathepsin K

Significance Fibrillar collagens constitute 90% of the organic bone matrix and are subjected either to physiological remodeling or excessive degradation during diseases such as osteoporosis. Cathepsin K is the critical collagenase in bone and represents a major antiresorptive drug target. Despite its critical role in bone remodeling, its mechanism of collagen degradation remained elusive. Here, we demonstrate that the degradation of fibrillar collagen requires the presence of a cathepsin K dimer bound at the surface of collagen fibers via glycosaminoglycans. Structural modifications of the protease dimerization site or the removal of collagen fiber-associated glycosaminoglycans specifically block fibrillar collagen degradation. The provided structure allows the development of a strategy to inhibit this highly relevant drug target in a substrate-specific manner.