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BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells.

ABSTRACT: Bone morphogenetic proteins (BMPs) activate the canonical Smad1/5/8 and non-canonical Tak1-MAPK pathways via BMP receptors I and II to regulate skeletal development and bone remodeling. Specific ablation of Bmpr1a in immature osteoblasts, osteoblasts, or osteocytes results in an increase in cancellous bone mass, yet opposite results have been reported regarding the underlying mechanisms. Moreover, the role for BMPRIA-mediated signaling in bone marrow mesenchymal stromal cells (BM-MSCs) has not been explored. Here, we specifically ablated Bmpr1a in BM-MSCs in adult mice to study the function of BMPR1A in bone remodeling and found that the mutant mice showed an increase in cancellous and cortical bone mass, which was accompanied by a decrease in bone formation rate and a greater decrease in bone resorption. Decreased bone formation was associated with a defect in BM-MSC osteogenic differentiation whereas decreased bone resorption was associated with a decrease in RANKL production and osteoclastogenesis. However, ablation of Tak1, a critical non-canonical signaling molecule downstream of BMP receptors, in BM-MSCs at adult stage did not affect bone remodeling. These results suggest that BMP signaling through BMPRIA controls BM-MSC osteogenic differentiation/bone formation and RANKL expression/osteoclastogenesis in adult mice independent of Tak1 signaling.

SUBMITTER: Biswas S

PROVIDER: S-EPMC5981611 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells.

Biswas Soma S Li Ping P Wu Hongguang H Shafiquzzaman Md M Murakami Shunichi S Schneider Michael D MD Mishina Yuji Y Li Baojie B Li Jing J

Scientific reports 20180531 1

Bone morphogenetic proteins (BMPs) activate the canonical Smad1/5/8 and non-canonical Tak1-MAPK pathways via BMP receptors I and II to regulate skeletal development and bone remodeling. Specific ablation of Bmpr1a in immature osteoblasts, osteoblasts, or osteocytes results in an increase in cancellous bone mass, yet opposite results have been reported regarding the underlying mechanisms. Moreover, the role for BMPRIA-mediated signaling in bone marrow mesenchymal stromal cells (BM-MSCs) has not b ...[more]

PMID: 29855498

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Project description:Previous studies have shown that platelet concentrates used in conjunction with appropriate growth media enhance osteogenic differentiation of human mesenchymal stromal cells (hMSCs). However, their potential in inducing osteogenesis of hMSCs when cultured in serum free medium has not been explored. Furthermore, the resulting osteogenic molecular signatures of the hMSCs have not been compared to standard osteogenic medium. We studied the effect of infrequent supplementation (8-day interval) of 15% non-activated platelet-rich concentrate (PRC) in serum free medium on hMSCs proliferation and differentiation throughout a course of 24 days, and compared the effect with those cultured in a standard osteogenic medium (OM). Cell proliferation was analyzed by alamar blue assay. Gene expression of osteogenic markers (Runx2, Collagen1, Alkaline Phosphatase, Bone morphogenetic protein 2, Osteopontin, Osteocalcin, Osteonectin) were analyzed using Q-PCR. Immunocytochemical staining for osteocalcin, osteopontin and transcription factor Runx2 were done at 8, 16 and 24 days. Biochemical assays for the expression of ALP and osteocalcin were also performed at these time-points. Osteogenic differentiation was further confirmed qualitatively by Alizarin Red S staining that was quantified using cetylpyridinium chloride. Results showed that PRC supplemented in serum free medium enhanced hMSC proliferation, which peaked at day 16. The temporal pattern of gene expression of hMSCs under the influence of PRC was comparable to that of the osteogenic media, but at a greater extent at specific time points. Immunocytochemical staining revealed stronger staining for Runx2 in the PRC-treated group compared to OM, while the staining for Osteocalcin and Osteopontin were comparable in both groups. ALP activity and Osteocalcin/DNA level were higher in the PRC group. Cells in the PRC group had similar level of bone mineralization as those cultured in OM, as reflected by the intensity of Alizarin red stain. Collectively, these results demonstrate a great potential of PRC alone in inducing proliferation of hMSCs without any influence from other lineage-specific growth media. PRC alone has similar capacity to enhance hMSC osteogenic differentiation as a standard OM, without changing the temporal profile of the differentiation process. Thus, PRC could be used as a substitute medium to provide sufficient pool of pre-differentiated hMSCs for potential clinical application in bone regeneration.

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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BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells.

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BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells.

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