image: (A) Real-time PCR analysis showed the effect of BMP9 on SIRT5 mRNA expression levels in MEFs. (B) Western blot assays showed the influence of BMP9 on SIRT5 protein levels in MEFs. (C) Quantitative analysis of Western blot data highlighted the impact of BMP9 on SIRT5 protein abundance in MEFs. (D) Real-time PCR results showed the endogenous SIRT5 mRNA expression patterns in various progenitor cell types. (E) Fluorescent and phase images showed the infection results of recombinant adenoviruses (a: AdBMP9, b: AdSIRT5, c: AdsiSIRT5), Western blot results showed the effects of recombinant adenoviruses on the protein level of targets (d: AdBMP9, e: AdSIRT5, f: AdsiSIRT5), and quantitative results of Western blot assay showed the effects of recombinant adenoviruses on the protein level of targets (g: AdBMP9, h: AdSIRT5, i: AdsiSIRT5). Scale bar = 200 μm ∗p < 0.05 and ∗∗p < 0.01 versus control. BMP9, bone morphogenetic protein 9; SIRT5, sirtuin 5; MEFs, mouse embryonic fibroblasts.
Credit: Genes & Diseases
Bone morphogenetic proteins (BMP), particularly BMP9, exhibits remarkable osteogenic potential. Both hypoxia-inducible factor 1 subunit alpha (HIF-1α) and sirtuin 5 (SIRT5) have been shown to enhance BMP9-induced osteogenic differentiation. However, it remains unclear whether HIF-1α is involved in the mechanism by which SIRT5 promotes BMP9’s osteogenic activity.
This research, published in the Genes & Diseases journal by a team from Chongqing Medical University, investigates the potential role of SIRT5 in enhancing BMP9's osteogenic capacity in mouse embryonic fibroblasts (MEFs) and deciphers the underlying molecular pathways.
Initial investigations using real-time quantitative PCR and western blot assays showed that BMP9 significantly increases SIRT5 expression in MEFs. Functional assays showed that overexpression of SIRT5 amplified BMP9-induced markers of bone formation, such as RUNX2, alkaline phosphatase (ALP) activity, and mineralization. Conversely, silencing SIRT5 reduced these osteogenic effects, indicating the pivotal positive role of SIRT5 in regulating BMP9’s osteogenic potential.
Further investigations showed that BMP9’s ability to increase HIF-1α protein levels was enhanced by exogenous SIRT5 but reduced by SIRT5 knockdown. Notably, the reduction in BMP9-induced osteogenic markers following SIRT5 silencing was mostly restored by exogenous HIF-1α supplementation. In contrast, silencing HIF-1α attenuated SIRT5’s ability to increase the levels of BMP9-induced osteogenic markers. A bone defect repair assay further confirmed the crucial role of HIF-1α in mediating the effects of SIRT5 on promoting the osteogenic capability of BMP9.
Importantly, the acetylation and malonylation levels of HIF-1α were reduced by SIRT5, which may enhance its stability and promote BMP9's osteogenic effect. Conversely, SIRT5 knockdown reversed these effects and promoted the degradation of HIF-1α.
In conclusion, this study demonstrates that BMP9's osteogenic potential could be promoted by SIRT5, potentially through stabilizing HIF-1α by reducing its acetylation and malonylation modification. Overall, the findings of this research provide new insights into the molecular regulation of BMP9-mediated osteogenesis and suggest that targeting SIRT5 could be a promising strategy to enhance bone tissue engineering for clinical applications.
Reference
Title of Original Paper: SIRT5 promotes the osteo-inductive potential of BMP9 by stabilizing the HIF-1α protein in mouse embryonic fibroblasts
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101563
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