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.

Liver-Directed Human Amniotic Epithelial Cell Transplantation Improves Systemic Disease Phenotype in Hurler Syndrome Mouse Model

“…Previous studies have shown that excess GAG accumulation inhibits the degradation of collagen type II by cathepsin K, resulting in impaired osteoclast activity and decreased cartilage resorption. This contributes to the skeletal abnormalities seen in the MPS1 human disease and the mouse model 43, 44. Significant normalization of bone volume and density values in our treated mice is further evidence of the therapeutic reduction of systemic GAGs achieved via liver‐directed hAEC transplantation.…”

Closed Meningo(encephalo)cele: A New Feature in Hunter Syndrome

“…2 The storage of GAGS in growing cartilage is thought to cause a bone maturation defect characterized by impaired osteoclast activity and decreased cartilage reabsorption. 16 Closed cephaloceles could represent a further manifestation of the pathologic process that affects the whole skeletal system in MPS. Of note, these abnormalities have been found in sites most frequently involved in skull defects in the general population.…”

Brain and Spinal MR Imaging Findings in Mucopolysaccharidoses: A Review

“…One finding described in several patients with MPS is the presence of pituitary sella abnormalities, found in MPS I, 51 have demonstrated a dysfunction of bone maturation in an MPS animal model, which may account for the above-mentioned skull deformities. Moreover, an enlarged pituitary gland was found in a child with MPS IIIA who had precocious puberty.…”

“…51 Thus, spinal MR imaging demonstrates various abnormalities concerning the vertebral bodies and intersomatic disks (Fig 6). Characteristic features are platyspondylia, and bullet shape and beaking of vertebrae, while disks were described as dehydrated.…”