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The present study investigated the synergistic effect of co‑administering fibroblast growth factor‑2 (FGF‑2) and bone morphogenetic protein‑2 (BMP‑2) on osteoblastic differentiation in C2C12 cells and in rats. C2C12 murine myoblast cells represent a well‑accepted in vitro model system to study the ability of BMP‑2 to alter cell lineage from the myogenic to the osteogenic phenotype. The osteoblastic differentiation potency was determined by alkaline phosphatase (ALP) and Alizarin red S staining. ALP activity and calcium concentrations were colorimetrically measured. Simultaneous administration of 4 µg/ml recombinant human BMP‑2 with 2 ng/ml FGF‑2 markedly enhanced ALP activity (an early marker of osteogenesis) of C2C12 cells. This combination also increased extracellular signal‑regulated kinase1/2 mitogen activated protein kinase signaling that is involved in the promoting effect of FGF‑2 on BMP‑2‑induced osteoblastic differentiation in C2C12 cells. Calcium deposition (a late marker of osteogenesis) and the expression of CD34 (a marker of new vessels) were promoted optimally by simultaneous local sustained administration of FGF‑2 and BMP‑2 using collagen and chitosan‑coated antigen‑extracted porcine cancellous implants in a rat ectopic implantation model. The synergistic effects of a combination of BMP‑2 and FGF‑2 may have potential for bone regenerative therapeutics.

The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ERα-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by BMP2 was significant. In MDA-MB-231 cells which are ERα-66-negative, BMP2 was able to induce the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ERα-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB‑231 cells was stimulated by 17-β-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ERα-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs.

Bone morphogenetic proteins (BMPs) are involved in diverse biological processes, including cell proliferation, differentiation and apoptosis. Results from the MTT assay revealed that BMP-2 significantly inhibited the proliferation of MDA-MB‑231 and MCF-7 breast cancer cells. The flow cytometric analysis demonstrated that BMP-2 caused G1 arrest and promoted apoptosis. An increase in p21 and cleaved caspase-3 in the two cell lines was detected by western blot analysis, which may be responsible for the suppression of cancer cell proliferation caused by BMP-2. BMP-2 protected MDA-MB-231 and MCF-7 cells from generating xenograft tumors in nude mice. Thus, BMP-2 may be considered as an inhibitor of breast cancer at the early stages of disease.