Abstract
BackgroundBone regenerative heterodimeric bone morphogenetic protein 2/7 (BMP2/7) enhances but all-trans retinoic acid (ATRA) inhibits osteoclastogenesis. However, the effect of ATRA on physiological and/or BMP2/7-induced osteoclastogenesis in still unclear. In this study, we aimed to test the effect of combined treatment of BMP2/7 and ATRA on osteoclastogenesis, and resorption activity.ResultsAll-trans retinoic acid (1 µM) ± BMP2/7 (5 or 50 ng/ml) was added in murine pre-osteoclasts cell line RAW264.7 or mouse bone marrow derived macrophages (BMM) cultures. Osteoclast marker gene expression, osteoclastogenesis, and resorption activity were analyzed. BMP2/7 robustly enhanced osteoclast maker gene expression, osteoclastogenesis, and resorption activity. Interestingly, ATRA completely inhibited osteoclast formation in presence or absence of BMP2/7. Pan-antagonist of retinoic acid receptors (RARs) and antagonist of RARα, β or γ failed to reverse the inhibitory effect of ATRA on osteoclastogenesis. ATRA strongly inhibited Rank and Nfatc1 expression.ConclusionsAll-trans retinoic acid inhibits BMP2/7-induced osteoclastogenesis, and resorption activity possibly via RANKL–RANK pathway. Our findings from previous and current study suggest that combination of ATRA and BMP2/7 could be a novel approach to treat hyperactive osteoclast-induced bone loss such as in inflammation-induced severe osteoporosis and bone loss caused by cancer metastasis to bone.
Highlights
Bone regenerative heterodimeric bone morphogenetic protein 2/7 (BMP2/7) enhances but all-trans retinoic acid (ATRA) inhibits osteoclastogenesis
We reported that BMP2/7 heterodimer at low-dose (5–50 ng/ml), in one hand, robustly enhances osteogenic differentiation compared to BMP2 or BMP7 homodimer alone [13], in other hand, enhances the RANKL-mediated osteoclastogenesis [14]
Cell proliferation was lower in ATRA + BMP2/7 (5 ng/ml), ATRA + BMP2/7 (50 ng/ ml) groups compared to BMP2/7 (5 ng/ml) and BMP2/7 (50 ng/ml) group respectively (Fig. 1a)
Summary
Bone regenerative heterodimeric bone morphogenetic protein 2/7 (BMP2/7) enhances but all-trans retinoic acid (ATRA) inhibits osteoclastogenesis. We reported that BMP2/7 heterodimer at low-dose (5–50 ng/ml), in one hand, robustly enhances osteogenic differentiation compared to BMP2 or BMP7 homodimer alone [13], in other hand, enhances the RANKL-mediated osteoclastogenesis [14]. This double edge sword like property of BMP2/7 heterodimer is a serious concern about the use of it as a therapeutic agent for bone regeneration during osteoclast-induced bone loss.
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