Failures of Endochondral Ossification in the Mucopolysaccharidoses

Abstract

Purpose of review: The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. MPS patients frequently exhibit failures of endochondral ossification during postnatal growth leading to skeletal deformity and short stature. In this review, we outline the current understanding of the cellular and molecular mechanisms underlying failures of endochondral ossification in MPS and discuss associated treatment challenges and opportunities.

Recent findings: Studies in MPS patients and animal models have demonstrated that skeletal cells and tissues exhibit significantly elevated GAG storage from early in postnatal life and that this is associated with impaired cartilage-to-bone conversion in primary and secondary ossification centers, and growth plate dysfunction. Recent studies have begun to elucidate the underlying cellular and molecular mechanisms, including impaired chondrocyte proliferation and hypertrophy, diminished growth factor signaling, disrupted cell cycle progression, impaired autophagy, and increased cell stress and apoptosis. Current treatments such as hematopoietic stem cell transplantation and enzyme replacement therapy fail to normalize endochondral ossification in MPS. Emerging treatments including gene therapy and small molecule-based approaches hold significant promise in this regard. Failures of endochondral ossification contribute to skeletal deformity and short stature in MPS patients, increasing mortality and reducing quality of life. Early intervention is crucial for effective treatment, and there is a critical need for new approaches that normalize endochondral ossification by directly targeting affected cells and signaling pathways.

Keywords: Endochondral ossification; Growth plate; Lysosomal storage disorder; Mucopolysaccharidosis; Short stature; Skeletal deformity.

Figure 1.

Representative transmission electron microscopy images showing accumulation of lysosomal storage in canine MPS VII resting, proliferating and hypertrophic chondrocytes in the vertebral epiphyseal growth plate (A-C), and in osteoblasts, osteoclasts and osteocytes in vertebral metaphyseal bone (D-F). Asterisks indicate vacuoles, which are enlarged lysosomes that were filled with storage material. Methods: Thoracic vertebral bodies obtained postmortem from 9-day-old MPS VII dogs were fixed in glutaraldehyde/paraformaldehyde and decalcified in formic acid and EDTA k. Samples were then post-fixed in osmium, dehydrated and embedded. Ultrathin (80 nm) sections were stained with uranyl acetate and lead citrate and examined using transmission electron microscopy (JEOL 1010; JEOL Ltd; Tokyo, Japan fitted with a Hamamatsu digital camera; Hamamatsu Corporation; Shizuoka, Japan; and AMT Advantage NanoSprint500 software; Advanced Microscopy Techniques; Woburn, USA). Studies were conducted following Institution Animal Care and Use Committee approval.

Figure 2.

Schematic representations of: A. The normal process of endochondral bone formation; and B. Failures of endochondral ossification frequently observed in MPS patients and animal models. It should be noted that bone disease manifestations and their severities vary both within and between MPS subtypes (see text for details). POC: primary ossification center; SOC: secondary ossification center; RC: resting chondrocytes; PC: proliferating chondrocytes; HC: hypertrophic chondrocytes; and BMD: bone mineral density. Elements used in this figure are adopted from Smart Medical Art (https://smart.servier.com/).