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LMCD1 promotes osteogenic differentiation of human bone marrow stem cells by regulating BMP signaling.

ABSTRACT: Human bone marrow stem cells (BMSCs) are heterogeneous progenitor cells with two defining features, self-renew and multi-lineage differentiation. As one of the differentiation directions, osteogenesis is vital for bone homeostasis. A growing body of evidences show that ubiquitin-dependent protein degradation plays an essential role in the osteogenic differentiation of BMSCs. In this study, we found that LMCD1 was upregulated during osteogenic differentiation process of BMSCs by analyzing GSE80614. In vitro and in vivo functional studies confirmed that LMCD1 was critical to the osteogenic commitment of BMSCs. Compared to those of the controls, downregulation of LMCD1 significantly restrained osteogenic differentiation and enhanced adipogenic differentiation, while upregulation of LMCD1 increased the osteogenic differentiation and suppressed adipogenic differentiation. Mechanically, we found that LMCD1 could protect RUNX2 and Smad1 protein from Smurf1-induced ubiquitination degradation thereby regulating BMP signaling. In conclusion, our findings suggest that LMCD1 is a novel regulator of osteogenic differentiation and may be a potential therapeutic target for bone metabolism related diseases.

SUBMITTER: Zhu B

PROVIDER: S-EPMC6733937 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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LMCD1 promotes osteogenic differentiation of human bone marrow stem cells by regulating BMP signaling.

Zhu Bin B Xue Feng F Zhang Changqing C Li Guangyi G

Cell death & disease 20190909 9

Human bone marrow stem cells (BMSCs) are heterogeneous progenitor cells with two defining features, self-renew and multi-lineage differentiation. As one of the differentiation directions, osteogenesis is vital for bone homeostasis. A growing body of evidences show that ubiquitin-dependent protein degradation plays an essential role in the osteogenic differentiation of BMSCs. In this study, we found that LMCD1 was upregulated during osteogenic differentiation process of BMSCs by analyzing GSE8061 ...[more]

PMID: 31501411

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Project description:BackgroundSubchondral bone sclerosis is a major feature of osteoarthritis (OA), and bone marrow mesenchymal stem cells (BMSCs) are presumed to play an important role in subchondral bone sclerosis. Accumulating evidence has shown that stromal cell-derived factor-1α (SDF-1α) plays a key role in bone metabolism-related diseases, but its role in OA pathogenesis remains largely unknown. The purpose of this study was to explore the role of SDF-1α expressed on BMSCs in subchondral bone sclerosis in an OA model.MethodsIn the present study, C57BL/6J mice were divided into the following three groups: the sham control, destabilization of the medial meniscus (DMM), and AMD3100-treated DMM (DMM + AMD3100) groups. The mice were sacrificed after 2 or 8 weeks, and samples were collected for histological and immunohistochemical analyses. OA severity was assessed by performing hematoxylin and eosin (HE) and safranin O-fast green staining. SDF-1α expression in the OA model was measured using an enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (q-PCR), and immunohistochemistry. Micro-CT was used to observe changes in subchondral bone in the OA model. CD44, CD90, RUNX2, and OCN expression in subchondral bone were measured using q-PCR and immunohistochemistry. In vitro, BMSCs were transfected with a recombinant lentivirus expressing SDF-1α, an empty vector (EV), or siRNA-SDF-1α. Western blot analysis, q-PCR, and immunofluorescence staining were used to confirm the successful transfection of BMSCs. The effect of SDF-1α on BMSC proliferation was evaluated by performing a CCK-8 assay and cell cycle analysis. The effect of SDF-1α on the osteogenic differentiation of BMSCs was assessed by performing alkaline phosphatase (ALP) and alizarin red S (ARS) staining. Cyclin D1, RUNX2 and OCN expression were measured using Western blot analysis, q-PCR, and immunofluorescence staining.ResultsSDF-1α expression in the DMM-induced OA model increased. In the DMM + AMD3100 group, subchondral bone sclerosis was alleviated, OA was effectively relieved, and CD44, CD90, RUNX2, and OCN expression in subchondral bone was decreased. In vitro, high levels of SDF-1α promoted BMSC proliferation and increased osteogenic differentiation. Cyclin D1, RUNX2, and OCN expression increased.ConclusionThe results of this study reveal a new molecular mechanism underlying the pathogenesis of OA. The targeted regulation of SDF-1α may be clinically effective in suppressing OA progression.

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LMCD1 promotes osteogenic differentiation of human bone marrow stem cells by regulating BMP signaling.

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LMCD1 promotes osteogenic differentiation of human bone marrow stem cells by regulating BMP signaling.

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