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Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice.

ABSTRACT: During skeletal development and regeneration, bone-forming osteoblasts respond to high metabolic demand by active expansion of their rough endoplasmic reticulum (rER) and increased synthesis of type I collagen, the predominant bone matrix protein. However, the molecular mechanisms that orchestrate this response are not well understood. We show that insertional mutagenesis of the previously uncharacterized osteopotentia (Opt) gene disrupts osteoblast function and causes catastrophic defects in postnatal skeletal development. Opt encodes a widely expressed rER-localized integral membrane protein containing a conserved SUN (Sad1/Unc-84 homology) domain. Mice lacking Opt develop acute onset skeletal defects that include impaired bone formation and spontaneous fractures. These defects result in part from a cell-autonomous failure of osteoblast maturation and a posttranscriptional decline in type I collagen synthesis, which is concordant with minimal rER expansion. By identifying Opt as a crucial regulator of bone formation in the mouse, our results uncover a novel rER-mediated control point in osteoblast function and implicate human Opt as a candidate gene for brittle bone disorders.

SUBMITTER: Sohaskey ML

PROVIDER: S-EPMC2867309 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice.

Sohaskey Michael L ML Jiang Yebin Y Zhao Jenny J JJ Mohr Andreas A Roemer Frank F Harland Richard M RM

The Journal of cell biology 20100501 3

During skeletal development and regeneration, bone-forming osteoblasts respond to high metabolic demand by active expansion of their rough endoplasmic reticulum (rER) and increased synthesis of type I collagen, the predominant bone matrix protein. However, the molecular mechanisms that orchestrate this response are not well understood. We show that insertional mutagenesis of the previously uncharacterized osteopotentia (Opt) gene disrupts osteoblast function and causes catastrophic defects in po ...[more]

PMID: 20440000

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Project description:The WNT/?-catenin signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. Although the importance of ?-catenin signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate ?-catenin in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for ?-catenin in committed growth-plate chondrocytes has been less robust. To identify the specific role of cartilage-derived ?-catenin in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2Cre(ERT2) transgene in combination with ?-catenin(fx(exon3)/wt) or ?-catenin(fx/fx) floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific ?-catenin signaling promotes chondrocyte maturation, possibly involving a bone morphogenic protein 2 (BMP2)-mediated mechanism. Second, cartilage-specific ?-catenin facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced matrix metalloproteinase (MMP) expression at sites of cartilage degradation, and potentially by enhancing Indian hedgehog (IHH) signaling activity to recruit vascular tissues. Finally, cartilage-specific ?-catenin signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived ?-catenin signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation.

Dataset Information

Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice.

Publications

Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice.

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