Cell biology of osteochondromas: Bone morphogenic protein signalling and heparan sulphates

Abstract

Frequent benign outgrowths from bone known as osteochondromas, exhibiting typical endochondral ossification, are reported from single to multiple lesions. Characterised by a high incidence of osteochondromas and skeletal deformities, multiple hereditary exostoses (MHE) is the most common inherited musculoskeletal condition. While factors for severity remain unknown, mutations in exostosin 1 and exostosin 2 genes, encoding glycosyltransferases involved in the biosynthesis of ubiquitously expressed heparan sulphate (HS) chains, are associated with MHE. HS-binding bone morphogenetic proteins (BMPs) are multifunctional proteins involved in the morphogenesis of bone and cartilage. HS and HS proteoglycans are involved in BMP-mediated morphogenesis by regulating their gradient formation and activity. Mutations in exostosin genes disturb HS biosynthesis, subsequently affecting its functional role in the regulation of signalling pathways. As BMPs are the primordial morphogens for bone development, we propose the hypothesis that BMP signalling may be critical in osteochondromas. For this reason, the outcomes of exostosin mutations on HS biosynthesis and interactions within osteochondromas and MHE are reviewed. Since BMPs are HS binding proteins, the interactions of HS with the BMP signalling pathway are discussed. The impact of mouse models in the quest to better understand the cell biology of osteochondromas is discussed. Several challenges and questions still remain and further investigations are needed to explore new approaches for better understanding of the pathogenesis of osteochondromas.

Osteochondromas in fibrodysplasia ossificans progressiva: a widespread trait with a streaking but overlooked appearance when arising at femoral bone end

“…All together, these data demonstrate that overactive BMP signaling pathway affects normal skeletal development at multiple stages, playing a key role on the pathogenesis of developmental FOP-associated skeletal malformations [45]. Furthermore, the unveiling of BMPs as the key morphogens for bone modelling renders BMP signaling as a critical regulator in the pathogenesis of osteochondroma and might allow classifying FOP disease among osteochondroma-related conditions, alongside hereditary multiple exostoses [46]. Understanding the molecular and genetic basis of these abnormalities does not only offer hope for FOP patients and their families, but also contribute to unravel the underlying basis of the development of the human musculoskeletal system.…”

A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers

“…The exostosin family of genes encodes glycosyltransferases that are responsible for the synthesis and assembly of heparan sulfate chains on proteoglycans . Both heparan sulfate and proteoglycans are critically important for normal bone and cartilage development . Because both EXT1 and EXT2 are required for heparan sulfate synthesis, heterozygous mutations in either gene results in systemic deficiency of these molecules in approximately 50% of patients with osteochondromatosis .…”

“…[28][29][30] Both heparan sulfate and proteoglycans are critically important for normal bone and cartilage development. 31,32 Because both EXT1 and EXT2 are required for heparan sulfate synthesis, heterozygous mutations in either gene results in systemic deficiency of these molecules in approximately 50% of patients with osteochondromatosis. 33 The exact mechanism by which mutations in EXT1 and EXT2 cause osteochondromatosis is unknown, however 2 theories have been advanced: haploinsufficiency and loss-ofheterozygosity (LOH).…”

Bone Graft Substitutes: Current Concepts and Future Expectations

“…17 In addition, there are concerns that BMPs may be pro-oncogenic and these agents are contraindicated in the setting of tumor extirpation. 18 Other disadvantages are their high cost and reports of immunogenicity to BMPs with resultant significant edema after off-label use in cervical spine surgery causing dysphagia and respiratory complications. Finally, the data that predicated the release of the rBMPs to market after U.S. Food and Drug Administration evaluation has been called into question with reports of inaccurate data reporting and undisclosed complications.…”