Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients

Benoist-Lasselin, Catherine; Margerie, Emmanuel de; Gibbs, Linda; Cormier, Sarah; Silve, Caroline; Nicolas, G.; LeMerrer, Martine; Mallet, J.-F.; Münnich, Arnold; Bonaventure, Jacky; Zylberberg, Louise; Legeai-Mallet, Laurence

doi:10.1016/j.bone.2005.12.003

Cited by 44 publications

(42 citation statements)

References 33 publications

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“…Homogeneous expression of Indian Hedgehog has been shown in osteochondromas, which is suggestive of autonomous cell signaling. 6 Therefore, correct orientation of the cilium is no longer needed to receive and transduce the diffusion gradient of Indian Hedgehog signaling. Other deregulated signaling pathways might also contribute to the misorientation of primary cilia.…”

Section: Cilia In Growth Plate and Osteochondroma Ce De Andrea Et Almentioning

confidence: 99%

“…Although the cells seem somewhat disorganized, the histological features of osteochondromas are similar to those of the growth plate. 6 Primary cilia are specialized cell surface projections present on most eukaryotic cells. 7,8 The primary cilium can be viewed as the antenna of the cell, which receives and transduces mechanical and chemical signals from the surrounding cells and the extracellular matrix.…”

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confidence: 99%

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Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

Andrea

Wiweger

Prins

et al. 2010

Laboratory Investigation

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Primary cilia are specialized cell surface projections found on most cell types. Involved in several signaling pathways, primary cilia have been reported to modulate cell and tissue organization. Although they have been implicated in regulating cartilage and bone growth, little is known about the organization of primary cilia in the growth plate cartilage and osteochondroma. Osteochondromas are bone tumors formed along the growth plate, and they are caused by mutations in EXT1 or EXT2 genes. In this study, we show the organization of primary cilia within and between the zones of the growth plate and osteochondroma. Using confocal and electron microscopy, we found that in both tissues, primary cilia have a similar formation but a distinct organization. The shortest ciliary length is associated with the proliferative state of the cells, as confirmed by Ki-67 immunostaining. Primary cilia organization in the growth plate showed that nonpolarized chondrocytes (resting zone) are becoming polarized (proliferating and hypertrophic zones), orienting the primary cilia parallel to the longitudinal axis of the bone. The alignment of primary cilia forms one virtual axis that crosses the center of the columns of chondrocytes reflecting the polarity axis of the growth plate. We also show that primary cilia in osteochondromas are found randomly located on the cell surface. Strikingly, the growth plate-like polarity was retained in sub-populations of osteochondroma cells that were organized into small columns. Based on this, we propose the existence of a mixture ('mosaic') of normal lining (EXT þ /À or EXT wt/wt ) and EXT À/À cells in the cartilaginous cap of osteochondromas.

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Section: Cilia In Growth Plate and Osteochondroma Ce De Andrea Et Almentioning

confidence: 99%

mentioning

confidence: 99%

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

Andrea

Wiweger

Prins

et al. 2010

Laboratory Investigation

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“…Currently, the factors that determine the severity of the disease are unknown. However, loss-of-function mutations in exostosin 1 (EXT1) and exostosin 2 (EXT2) genes have been identified as the causative agents in MHE [1,12,28,32,34].…”

Section: Multiple Hereditary Exostosesmentioning

confidence: 99%

“…Thus, functional HS synthesis requires both gene products. Mutations in either EXT1 or EXT2 genes lead to the synthesis of truncated EXT proteins, resulting in the formation of a defective EXT1/EXT2 complex that disturbs HS synthesis [1,3,12,39]. Truncated EXT proteins result in reduced co-polymerase activity which leads to the production of short HS chains [6,33].…”

Section: Exostosin and Heparan Sulfate Interactionmentioning

confidence: 99%

“…In normal growth plates hypertrophic chondrocytes do not proliferate but instead undergo apoptosis. Interestingly, the marker for proliferative cells proliferating cell nuclear antigen (PCNA) was detected in prehypertrophic and hypertrophic chondrocytes of osteochondromas while absent in hypertrophic chondrocytes of normal growth plates [1]. Nestin is a type VI intermediate filament protein expressed in proliferative neural cells during development.…”

Section: Mouse Models For Pathogenesismentioning

confidence: 99%

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

Cuellar

Reddi

2013

International Orthopaedics (SICOT)

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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.

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Molecular Genetics of Multiple Osteochondromas

Andrea

Hogendoorn

Bovée

2016

Encyclopedia of Life Sciences

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Multiple osteochondromas (MOs) is an autosomal dominant disease characterised by MOs (previously named exostoses). Their formation requires bi‐allelic inactivation of EXT1 or EXT2 genes in growth plate cartilage. They encode glycosyltransferases that catalyse the chain elongation step in heparan sulfate biosynthesis and when mutated cause a variety of growth factor signalling defects, impaired cell–matrix interactions and loss of polarity. Osteochondromas are not clonal neoplasms, but a mixed population of cells harbouring homozygous loss of either EXT genes or cells retaining the EXT wild‐type allele. About 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary chondrosarcoma. Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation, possibly by inactivation of the CDKN2A locus. This locus encodes INK4a (p16), which regulates RB1, and p19ARF, which regulates P53. Inactivation of CDKN2A by mutation or deletion is a common pathway for oncogenesis. Key Concepts Patients with MO are characterised genetically by germline mutations in EXT1 and EXT2 genes and phenotypically by the development of at least two osteochondromas. Osteochondroma is a benign cartilage‐capped bony projection arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone. Osteochondromas are the most frequent cartilaginous lesions, most often found on the femur (21%), humerus (17%) and tibia (11%). Somatic inactivation of both EXT alleles results in significantly shorter heparan sulfate chains. Defective heparan sulfate biosynthesis results in abnormal diffusion and signalling of IHH and FGFR3 causing increased proliferation and delayed differentiation. Approximately 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary peripheral chondrosarcoma. An osteochondroma cap exceeding 1.5–2 cm in adults is suggestive of malignancy. The most common location for malignant transformation of an osteochondroma is the pelvis, where large lesions can be difficult to excise completely. Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation. Secondary peripheral chondrosarcoma typically shows chromosome instability with gains and losses and genomic diversity that increases with increasing grade of malignancy. Loss of heterozygosity for the chromosomal bands bearing the RB1 and CDKN2A ( p16INK4a ) tumour suppressor genes is often found.

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Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients

Cited by 44 publications

References 33 publications

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma

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

Molecular Genetics of Multiple Osteochondromas

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