title: Regulatory role of stromal cell-derived factor-1 in bone morphogenetic protein-2-induced chondrogenic differentiation in vitro.
abstract: Chemokine stromal cell-derived factor-1 (SDF-1) signals via binding to its primary transmembrane receptor, cysteine (C)-X-C chemokine receptor-4 (CXCR4). We previously reported that SDF-1 regulates osteogenic differentiation of mesenchymal stem/progenitor cells (MPCs) induced by bone morphogenetic protein-2 (BMP2). Although BMP2 is also capable of inducing chondrogenic differentiation of MPCs, the involvement of SDF-1 signaling in this function of BMP2 remains unknown. In this study, we aimed to test the role of SDF-1 signaling involved in BMP2-induced chondrogenic differentiation, using ATDC5 chondroprogenitors and mouse bone marrow-derived mesenchymal stromal cells (BMSCs). Our data showed that blocking of the SDF-1/CXCR4 pathway inhibits the differentiation of these cells into the chondrocytic lineages in response to BMP2 stimulation, evidenced by the reduced expression of type II collagen α1 (Col2α1), aggrecan, and type X collagen α1 (Col10α1), markers for chondrogenic differentiation. This effect of blocking SDF-1 signaling on BMP2-chondrogenic differentiation is associated with suppressed Sox9 and Runx2 expression (key transcription factors required for early and late stages of chondrogenic differentiation, respectively) and mediated via inhibiting intracellular Smad and Erk activation. Moreover, we found that addition of exogenous SDF-1 protein synergistically enhances the BMP2-induced chondrogenic differentiation in a dose-dependent manner. Collectively, our results demonstrated a novel role of SDF-1 signaling in regulating BMP2-induced chondrogenic differentiation in vitro. These data provide new insights into molecular mechanisms underlying BMP2-osteo/chondrogenesis, and may lead to the identification of new therapeutic targets and strategies to improve cartilage repair and regeneration in broad orthopaedic situations.
authors: Musculoskeletal Integrity Program, Hospital for Special Surgery, New York, NY 10021, USA.
authors: Liang G
authors: LG
authors: Guang
authors: Adele L
authors: AL
authors: Boskey
authors: Wei
authors: W
authors: Zhu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000187:drug effects / Q000378:metabolism*; D020219:Chondrogenesis / Q000187:drug effects* / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019718:Receptors, CXCR4 / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D054377:Chemokine CXCL12; D050659:Core Binding Factor Alpha 1 Subunit; D019718:Receptors, CXCR4; C493716:Runx2 protein, mouse; D055758:SOX9 Transcription Factor; D051785:Smad Proteins; C527933:Sox9 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases