title: Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate.
abstract: Bone resorption in balance with bone formation is vital for the maintenance of the skeleton and is mediated by osteoclasts. Cathepsin K is the predominant protease in osteoclasts that degrades the bulk of the major bone forming organic component, type I collagen. Although the potent collagenase activity of cathepsin K is well known, its mechanism of action remains elusive. Here, we report a cathepsin K-specific complex with chondroitin sulfate, which is essential for the collagenolytic activity of the enzyme. The complex is an oligomer consisting of five cathepsin K and five chondroitin sulfate molecules. Only the complex exhibits potent triple helical collagen-degrading activity, whereas monomeric cathepsin K has no collagenase activity. The primary substrate specificity of cathepsin K is not altered by complex formation, suggesting that the protease-chondroitin sulfate complex primarily facilitates the destabilization and/or the specific binding of the triple helical collagen structure. Inhibition of complex formation leads to the loss of collagenolytic activity but does not impair the proteolytic activity of cathepsin K toward noncollagenous substrates. The physiological relevance of cathepsin K complexes is supported by the findings that (i) the content of chondroitin sulfate present in bone and accessible to cathepsin K activity is sufficient for complex formation and (ii) Y212C, a cathepsin K mutant that causes pycnodysostosis (a bone sclerosing disorder) and that has no collagenase activity but remains potent as a gelatinase, is unable to form complexes. These findings reveal a novel mechanism of bone collagen degradation and suggest that targeting cathepsin K complex formation would be an effective and specific treatment for diseases with excessive bone resorption such as osteoporosis.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, New York 10029, USA.
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Wu-Shiun
authors.initials: WS
authors.lastname: Hou
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Escalante-Torres
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Dieter
authors.initials: D
authors.lastname: Bromme
mesh_terms: D001842:Bone and Bones / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008027:Light; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D012542:Scattering, Radiation; D012598:Sclerosis / Q000235:genetics; D013379:Substrate Specificity; D013696:Temperature; D014461:Ultracentrifugation
chemical_list: D010455:Peptides; D002809:Chondroitin Sulfates; D003094:Collagen; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; D017364:Collagenases