Failures of Endochondral Ossification in the Mucopolysaccharidoses
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RARE BONE DISEASE (CB LANGMAN AND E SHORE, SECTION EDITORS)
Failures of Endochondral Ossification in the Mucopolysaccharidoses Zhirui Jiang 1,2 & Sharon Byers 3,4,5 & Margret L. Casal 6 & Lachlan J. Smith 1,2 Accepted: 29 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Summary 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 Short stature . Endochondral ossification . Mucopolysaccharidosis . Growth plate . Skeletal deformity . Lysosomal storage disorder
Introduction This article is part of the Topical Collection on Rare Bone Disease * Lachlan J. Smith [email protected] 1
Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2
Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, 371 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104, USA
3
Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
4
Paediatrics, The University of Adelaide, Adelaide, SA, Australia
5
Genetics and Evolution, The University of Adelaide, Adelaide, SA, Australia
6
Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
Overview of the Mucopolysaccharidoses The m
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