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Deletion of BMP receptor type IB decreased bone mass in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors.

ABSTRACT: We previously found that disruption of two type I BMP receptors, Bmpr1a and Acvr1, respectively, in an osteoblast-specific manner, increased bone mass in mice. BMPR1B, another BMP type I receptor, is also capable of binding to BMP ligands and transduce BMP signaling. However, little is known about the function of BMPR1B in bone. In this study, we investigated the bone phenotype in Bmpr1b null mice and the impacts of loss of Bmpr1b on osteoblasts and osteoclasts. We found that deletion of Bmpr1b resulted in osteopenia in 8-week-old male mice, and the phenotype was transient and gender specific. The decreased bone mass was neither due to the changes in osteoblastic bone formation activity nor osteoclastic bone resorption activity in vivo. In vitro differentiation of Bmpr1b null osteoclasts was increased but resorption activity was decreased. Calvarial pre-osteoblasts from Bmpr1b mutant showed comparable differentiation capability in vitro, while they showed increased BMP-SMAD signaling in culture. Different from calvarial pre-osteoblasts, Bmpr1b mutant bone marrow mesenchymal progenitors showed compromised differentiation in vitro, which may be a reason for the osteopenic phenotype in the mutant mice. In conclusion, our results suggested that BMPR1B plays distinct roles from BMPR1A and ACVR1 in maintaining bone mass and transducing BMP signaling.

SUBMITTER: Shi C

PROVIDER: S-EPMC4822175 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Deletion of BMP receptor type IB decreased bone mass in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors.

Shi Ce C Iura Ayaka A Terajima Masahiko M Liu Fei F Lyons Karen K Pan Haichun H Zhang Honghao H Yamauchi Mitsuo M Mishina Yuji Y Sun Hongchen H

Scientific reports 20160406

We previously found that disruption of two type I BMP receptors, Bmpr1a and Acvr1, respectively, in an osteoblast-specific manner, increased bone mass in mice. BMPR1B, another BMP type I receptor, is also capable of binding to BMP ligands and transduce BMP signaling. However, little is known about the function of BMPR1B in bone. In this study, we investigated the bone phenotype in Bmpr1b null mice and the impacts of loss of Bmpr1b on osteoblasts and osteoclasts. We found that deletion of Bmpr1b ...[more]

PMID: 27048979

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Project description:BackgroundOsteogenesis Imperfecta (OI) (OMIM %259450) is a heterogeneous group of inherited disorders characterized by increased bone fragility, with clinical severity ranging from mild to lethal. The majority of OI cases are caused by mutations in COL1A1 or COL1A2. Bruck Syndrome (BS) is a further recessively-inherited OI-like phenotype in which bone fragility is associated with the unusual finding of pterygia and contractures of the large joints. Notably, several studies have failed to show any abnormalities in the biosynthesis of collagen 1 in BS patientes. Evidence was obtained for a specific defect of the procollagen telopeptide lysine hydroxylation in BS, whereas mutations in the gene PLOD2 have been identified. Recently, several studies described FKBP10 mutations in OI-like and BS patients, suggesting that FKBP10 is a bonafide BS locus.MethodsWe analyzed the coding region and intron/exon boundaries of COL1A1, COL1A2, PLOD2 and FKBP10 genes by sequence analysis using an ABI PRISM 3130 automated sequencer and Big Dye Terminator Sequencing protocol. Mononuclear cells obtained from the bone marrow of BS, OI patients and healthy donors were cultured and osteogenic differentiation was induced. The gene expression of osteoblast specific markers were also evaluated during the osteoblastic differentiation of mesenchymal stem cell (MSC) by qRT-PCR using an ABI7500 Sequence Detection System.ResultsNo mutations in COL1A1, COL1A2 or PLOD2 were found in BS patient. We found a homozygous 1-base-pair duplication (c.831dupC) that is predicted to produce a translational frameshift mutation and a premature protein truncation 17 aminoacids downstream (p.Gly278ArgfsX95). The gene expression of osteoblast specific markers BGLAP, COL1A1, MSX2, SPARC and VDR was evaluated by Real Time RT-PCR during differentiation into osteoblasts and results showed similar patterns of osteoblast markers expression in BS and healthy controls. On the other hand, when compared with OI patients, the expression pattern of these genes was found to be different.ConclusionsOur work suggests that the gene expression profiles observed during mesenchymal stromal cell differentiation into osteoblast are distinct in BS patients as compared to OI patients. The present study shows for the first time that genes involved in osteogenesis are differentially expressed in BS and OI patients.

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Deletion of BMP receptor type IB decreased bone mass in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors.

Publications

Deletion of BMP receptor type IB decreased bone mass in association with compromised osteoblastic differentiation of bone marrow mesenchymal progenitors.

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