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

Andrea, Carlos E. de; Wiweger, Małgorzata; Prins, Frans A.; Bovée, Judith V.M.G.; Romeo, Salvatore; Hogendoorn, Pancras C.W.

doi:10.1038/labinvest.2010.81

Cited by 77 publications

(79 citation statements)

References 37 publications

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“…However, in the proliferating and hypertrophic chondrocytes, primary cilia are orientated parallel to the longitudinal axis of the bone ( Figure 1) [34]. The polarization of primary cilia in the proliferating and hypertrophic zones of the epiphyseal growth plate creates a virtual axis that crosses the centre of each column of stacked chondrocytes ( Figure 1).…”

Section: The Polarization Of the Epiphyseal Growth Platementioning

confidence: 99%

“…The polarization of primary cilia in the proliferating and hypertrophic zones of the epiphyseal growth plate creates a virtual axis that crosses the centre of each column of stacked chondrocytes ( Figure 1). The parallel ciliary axes across the epiphyseal growth plate seem to represent the planar polarity axis of the chondrocyte, and consequently of the entire epiphyseal growth plate [34].…”

Section: The Polarization Of the Epiphyseal Growth Platementioning

confidence: 99%

“…Recently, it has been shown that, in humans and in animal models, cells with functional EXT are being integrated into the osteochondroma cartilaginous cap [20,34,61,62]. These cells might be wild-type chondrocytes from the epiphyseal growth plate or stem cells from the neighbouring tissue.…”

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

“…Areas with reduced amount of proteoglycans with no gradient formation have probably chondrocytes with homozygous inactivation of EXT1/EXT2. It has been shown that cell polarity is lost in osteochondroma, which is reflected either by the random orientation of primary cilia in the tumour or the lack of these organelles in some osteochondroma cells [34]. Interestingly, the columns of stacked cells in osteochondroma retained the growth plate's cell polarity, in which primary cilia are aligned in a common axis, indicating the presence of wild-type chondrocytes in the tumour [34].…”

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

“…Cells with homozygous inactivation of EXT1/EXT2 lose their ability to respond to polarity signals [34]. Hypothetically, shorter heparan sulphate chains disrupt the polarity function of primary cilia in osteochondroma cells, which leads to loss of cell/tissue polarity.…”

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

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Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Andrea¹,

Hogendoorn²

2011

The Journal of Pathology

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Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM).Chondrocyte-matrix interactions compensate the lack of cell-cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the ECM, creating short-and long-range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell-matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and matrix proteoglycans. This disrupts the diffusion gradients of morphogens and signal transduction in the epiphyseal growth plate, contributing to loss of cell polarity and osteochondroma formation. Osteochondromas are cartilage-capped bony projections arising from the metaphyses of endochondral bones adjacent to the growth plate. The osteochondroma cap is formed by cells with homozygous mutation of EXT1/EXT2 and committed stem cells/wild-type chondrocytes. Osteochondroma serves as a niche (a permissive environment), which facilitates the committed stem cells/wild-type chondrocytes to acquire secondary genetic changes to form a secondary peripheral chondrosarcoma. In such a scenario, the micro-environment is the site of the initiating processes that ultimately lead to cancer.

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Section: The Polarization Of the Epiphyseal Growth Platementioning

confidence: 99%

Section: The Polarization Of the Epiphyseal Growth Platementioning

confidence: 99%

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

Section: A Propitious Micro-environment For Osteochondromagenesismentioning

confidence: 99%

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Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Andrea¹,

Hogendoorn²

2011

The Journal of Pathology

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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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Orientation of Primary Cilia of Articular Chondrocytes in Three‐Dimensional Space

Farnum

Wilsman

2011

The Anatomical Record

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Primary cilia have functions as sensory organelles integral to signal transduction and establishment of cell polarity. In articular cartilage the primary cilium has been hypothesized to function as an antenna to sense the biomechanical environment, regulate the secretion of extracellular matrix components, and maintain cellular positional information, leading to high tissue anisotropy. We used analysis of electron microscopy serial sections to demonstrate positional attributes of the primary cilium of adult equine articular chondrocytes in situ. Data for $500 axonemes, comparing superficial to radiate chondrocytes from both load-bearing and non-load-bearing regions, were graphed using spherical co-ordinates y, u. The data demonstrate the axoneme has a definable orientation in 3D space differing in superficial and radiate zone chondrocytes, cells that differ by 90 in the orientation of their major axes to the articular surface. Axonemal orientation is more definable in load-bearing than in non-loadbearing areas. The position of emergence of the axoneme from the cell also is variable. In load-bearing regions of the superficial zone, extension of the axoneme is from the cellular side facing the subchondral bone. In radiate zone cells, axonemes extend from either face of the chondrocyte, that is, both toward the articular surface or toward the subchondral bone. In non-load-bearing regions this consistency is lost. These observations relate to current hypotheses concerning establishment of tissue anisotropy in articular cartilage during development, involving both migration of cells from the joint periphery and a restricted zone of division within the tissue resulting in the columnar arrangement of radiate zone cells. Anat Rec, 294:533-549, 2011. V V C 2011 Wiley-Liss, Inc.

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

Cited by 77 publications

References 37 publications

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter

Molecular Genetics of Multiple Osteochondromas

Orientation of Primary Cilia of Articular Chondrocytes in Three‐Dimensional Space

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