Mucopolysaccharidoses (MPS) are autosomal recessive lysosomal storage diseases caused by deficiencies of enzymes involved in the degradation pathway of glycosaminoglycans (GAGs). Depending on the enzyme deficiency, affected cells accumulate dermatan sulfate, heparan sulfate, chondroitin sulfate, keratan sulfate or combinations thereof and the clinical phenotype varies with the nature of the accumulation product. Most MPS are characterized by profound skeletal abnormalities indicating malfunctions during bone and cartilage development and/or remodeling. The molecular mechanism why MPSs display severe bone abnormalities and how their phenotypes depend on the type of the GAGs accumulated is unknown. This application will focus on the potential involvement of cathepsin K in the disease mechanism of MPS. Cathepsin K is a lysosomal cysteine protease predominantly expressed in osteoclasts and fibroblasts and has been identified as the major bone and cartilage-degrading activity. This function is best documented by the finding that cathepsin K deficiency causes a severe bone dysplasia (pycnodysostosis). We have recently demonstrated that the collagenolytic activity of cathepsin K is differentially regulated by GAGs. Chondroitin- and keratan sulfates enhance the collagenolytic activity of the protease, while dermatan and heparan sulfates are potent inhibitors. These findings correlate well with the """"""""dysostosis multiplex"""""""" bone phenotype in MPSI, II, VI, and VII (accumulation of primarily DS and HS) and the partially """"""""osteoporotic"""""""" phenotype of MPSIV (accumulation of KS and CS). Thus, our main hypothesis is that GAG accumulation in MPS specifically affects the critical bone and cartilage resorbing activity of cathepsin K. Therefore, we will: 1) analyze and compare the bone pathologies in selected MPS and cathepsin K deficiency in human and mice and determine the effect of GAG accumulation on cathepsin K activity, 2) determine whether the overexpression of cathepsin K delays and deficiency in cathepsin K activity accelerates the bone pathology in MPSI mice, 3) determine the molecular and structural basis of the inhibition of cathepsin K activity by GAGs, and 4) elucidate novel approaches to interfere selectively with the binding of GAGs to cathepsin K as a novel approach for diseases with bone resorption defects (MPS and osteoporosis). Altogether, these studies should elucidate the impact of GAGs in MPS on bone resorption catalyzed by cathepsin K.
| Wilson, Susan; Bromme, Dieter (2010) Potential role of cathepsin K in the pathophysiology of mucopolysaccharidoses. J Pediatr Rehabil Med 3:139-146 |
| Wilson, Susan R; Peters, Christoph; Saftig, Paul et al. (2009) Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption. J Biol Chem 284:2584-92 |
| Wilson, Susan; Hashamiyan, Saadat; Clarke, Lorne et al. (2009) Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities. Am J Pathol 175:2053-62 |
| Selent, Jana; Kaleta, Jadwiga; Li, Zhenqiang et al. (2007) Selective inhibition of the collagenase activity of cathepsin K. J Biol Chem 282:16492-501 |
