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Originally published online as doi:10.2353/ajpath.2009.090211 on October 15, 2009

Published online before print October 15, 2009
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(American Journal of Pathology. 2009;175:2053-2062.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090211

Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

Susan Wilson*, Saadat Hashamiyan*, Lorne Clarke{dagger}, Paul Saftig{ddagger}, John Mort§, Valeria M. Dejica§ and Dieter Brömme*

From the Faculty of Dentistry,* University of British Columbia, Vancouver, Canada; the Department of Medical Genetics,{dagger} University of British Columbia, The British Columbia Institute for Child and Family Health, Vancouver, Canada; the Biochemisches Institut,{ddagger} Christian-Albrechts-Universität Kiel, Kiel, Germany; and the Shriner’s Hospital for Children and McGill University,§ Montreal, Canada

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.


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