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SDF-1? induces PDGF-B expression and the differentiation of bone marrow cells into pericytes.

ABSTRACT: Platelet-derived growth factor B (PDGF-B) and its receptor, PDGFR-?, play a critical role in pericyte maturation; however, the mechanisms by which PDGF-B is upregulated in the tumor microenvironment remain unclear. We previously showed that upregulating stromal-derived factor, SDF-1?, in VEGF(165)-inhibited Ewing's sarcoma tumors (TC/siVEGF(7-1)) induced PDGF-B mRNA expression, increased infiltration and differentiation of bone marrow cells (BMC) into pericytes and, rescued tumor growth. The purpose of this study was to investigate the mechanism by which SDF-1? increased PDGF-B expression and the role of this pathway in BM-derived pericyte differentiation. We showed that SDF-1? induced expression of PDGF-B mRNA and protein both in vitro and in vivo. In contrast, inhibiting SDF-1? downregulated PDGF-B. We cloned the 2-kb pdgf-b promoter fragment and showed that SDF-1? activates PDGF-B via a transcriptional mechanism. Chromatin immunoprecipitation showed that the ELK-1 transcription factor binds to the pdgf-b promoter in response to SDF-1?. We confirmed the correlation between the SDF-1?/PDGF-B pathway and the differentiation of PDGFR-?+ BMCs into mature pericytes using an in vitro assay. These findings show that SDF-1? regulates PDGF-B expression and that this regulation plays a critical role in the differentiation of PDGFR-?+ BMCs into mature pericytes.

SUBMITTER: Hamdan R

PROVIDER: S-EPMC3219839 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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SDF-1α induces PDGF-B expression and the differentiation of bone marrow cells into pericytes.

Hamdan Randala R Zhou Zhichao Z Kleinerman Eugenie S ES

Molecular cancer research : MCR 20110912 11

Platelet-derived growth factor B (PDGF-B) and its receptor, PDGFR-β, play a critical role in pericyte maturation; however, the mechanisms by which PDGF-B is upregulated in the tumor microenvironment remain unclear. We previously showed that upregulating stromal-derived factor, SDF-1α, in VEGF(165)-inhibited Ewing's sarcoma tumors (TC/siVEGF(7-1)) induced PDGF-B mRNA expression, increased infiltration and differentiation of bone marrow cells (BMC) into pericytes and, rescued tumor growth. The pur ...[more]

PMID: 21911740

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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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SDF-1? induces PDGF-B expression and the differentiation of bone marrow cells into pericytes.

Publications

SDF-1α induces PDGF-B expression and the differentiation of bone marrow cells into pericytes.

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