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Versican facilitates chondrocyte differentiation and regulates joint morphogenesis.

ABSTRACT: Versican/PG-M is a large chondroitin sulfate proteoglycan in the extracellular matrix, which is transiently expressed in mesenchymal condensation areas during tissue morphogenesis. Here, we generated versican conditional knock-out mice Prx1-Cre/Vcan(flox/flox), in which Vcan is pruned out by site-specific Cre recombinase driven by the Prx1 promoter. Although Prx1-Cre/Vcan(flox/flox) mice are viable and fertile, they develop distorted digits. Histological analysis of newborn mice reveals hypertrophic chondrocytic nodules in cartilage, tilting of the joint, and a slight delay of chondrocyte differentiation in digits. By immunostaining, whereas the joint interzone of Prx1-Cre/Vcan(+/+) shows an accumulation of TGF-beta, concomitant with versican, that of Prx1-Cre/Vcan(flox/flox) without versican expression exhibits a decreased incorporation of TGF-beta. In a micromass culture system of mesenchymal cells from limb bud, whereas TGF-beta and versican are co-localized in the perinodular regions of developing cartilage in Prx1-Cre/Vcan(+/+), TGF-beta is widely distributed in Prx1-Cre/Vcan(flox/flox). These results suggest that versican facilitates chondrogenesis and joint morphogenesis, by localizing TGF-beta in the extracellular matrix and regulating its signaling.

SUBMITTER: Choocheep K

PROVIDER: S-EPMC2898371 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Versican facilitates chondrocyte differentiation and regulates joint morphogenesis.

Choocheep Kanyamas K Hatano Sonoko S Takagi Hidekazu H Watanabe Hiroki H Kimata Koji K Kongtawelert Prachya P Watanabe Hideto H

The Journal of biological chemistry 20100419 27

Versican/PG-M is a large chondroitin sulfate proteoglycan in the extracellular matrix, which is transiently expressed in mesenchymal condensation areas during tissue morphogenesis. Here, we generated versican conditional knock-out mice Prx1-Cre/Vcan(flox/flox), in which Vcan is pruned out by site-specific Cre recombinase driven by the Prx1 promoter. Although Prx1-Cre/Vcan(flox/flox) mice are viable and fertile, they develop distorted digits. Histological analysis of newborn mice reveals hypertro ...[more]

PMID: 20404343

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Project description:Loss of PTPN11/SHP2 in mice or in human metachondromatosis (MC) patients causes benign cartilage tumors on the bone surface (exostoses) and within bones (enchondromas). To elucidate the mechanisms underlying cartilage tumor formation, we investigated the role of SHP2 in the specification, maturation and organization of chondrocytes. Firstly, we studied chondrocyte maturation by performing RNA-seq on primary chondrocyte pellet cultures. We found that SHP2 depletion, or inhibition of the ERK1/2 pathway, delays the terminal differentiation of chondrocytes from the early-hypertrophic to the late-hypertrophic stage. Secondly, we studied chondrocyte maturation and organization in mice with a mosaic postnatal inactivation of Ptpn11 in chondrocytes. We found that the vertebral growth plates of these mice have expanded domains of early-hypertrophic chondrocytes that have not yet terminally differentiated, and their enchondroma-like lesions arise from chondrocytes displaced from the growth plate due to a disruption in the organization of maturation and ossification zones. Furthermore, we observed that lesions from human MC patients also display disorganized chondrocyte maturation zones. Next, we found that inactivation of Ptpn11 in Fsp1-Cre-expressing fibroblasts induces exostosis-like outgrowths, suggesting that loss of SHP2 in cells on the bone surface and at bone-ligament attachment sites induces ectopic chondrogenesis. Finally, we performed lineage tracing to show that exostoses and enchondromas in mice likely contain mixtures of wild-type and SHP2-deficient chondrocytes. Together, these data indicate that in patients with MC, who are heterozygous for inherited PTPN11 loss-of-function mutations, second-hit mutations in PTPN11 can induce enchondromas by disrupting the organization and delaying the terminal differentiation of growth plate chondrocytes, and can induce exostoses by causing ectopic chondrogenesis of cells on the bone surface. Furthermore, the data are consistent with paracrine signaling from SHP2-deficient cells causing SHP2-sufficient cells to be incorporated into the lesions.

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Versican facilitates chondrocyte differentiation and regulates joint morphogenesis.

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Versican facilitates chondrocyte differentiation and regulates joint morphogenesis.

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