title: Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities.
abstract: Mucopolysaccharidoses are a group of lysosomal storage diseases characterized by the build-up of glycosaminoglycans (GAGs) and severe skeletal abnormalities. As GAGs can regulate the collagenolytic activity of the major osteoclastic protease cathepsin K, we investigated the presence and activity of cathepsin K and its co-localization with GAGs in mucopolysaccharidosis (MPS) type I bone. The most dramatic difference between MPS I and wild-type mice was an increase in the amount of cartilage in the growth plates in MPS I bones. Though the number of cathepsin K-expressing osteoclasts was increased in MPS I mice, these mice revealed a significant reduction in cathepsin K-mediated cartilage degradation. As excess heparan and dermatan sulfates inhibit type II collagen degradation by cathepsin K and the spatial overlap between cathepsin K and heparan sulfate strongly increased in MPS I mice, the build up of subepiphyseal cartilage is speculated to be a direct consequence of cathepsin K inhibition by MPS I-associated GAGs. Moreover, isolated MPS I and Ctsk(-/-) osteoclasts displayed fewer actin rings and formed fewer resorption pits on dentine disks, as compared with wild-type cells. These results suggest that the accumulation of GAGs in murine MPS I bone has an inhibitory effect on cathepsin K activity, resulting in impaired osteoclast activity and decreased cartilage resorption, which may contribute to the bone pathology seen in MPS diseases.
authors.affiliation: University of British Columbia, Vancouver, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Wilson
authors.forename: Saadat
authors.initials: S
authors.lastname: Hashamiyan
authors.forename: Lorne
authors.initials: L
authors.lastname: Clarke
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: John
authors.initials: J
authors.lastname: Mort
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Dejica
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
mesh_terms: D000818:Animals; D001862:Bone Resorption; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism*; D024043:Collagen Type II / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006132:Growth Plate / Q000002:abnormalities / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology
chemical_list: D024043:Collagen Type II; D006025:Glycosaminoglycans; D056657:Cathepsin K