Grem1 inhibits osteogenic differentiation of MBMSCs in OVX rats through BMP/Smad1/5 signaling pathway

Objective: This study aims to explore how Grem1 regulates the differentiation and signaling activity of mandibular bone marrow mesenchymal stem cells (MBMSCs), affecting their osteogenic differentiation capacity and participating in the pathophysiological mechanism of postmenopausal mandibular osteoporosis. Materials and methods: A postmenopausal osteoporosis (POP) rat model was constructed via bilateral ovariectomy. Techniques such as Western Blot (WB) and Real-Time Quantitative PCR (RT-qPCR) were employed to determine changes in Grem1 expression in MBMSCs of postmenopausal rats and its effect on osteogenic differentiation. Plasmids for Grem1 overexpression and siRNA for Grem1 knockdown were transfected into MBMSCs, and WB was used to assess the regulatory role of Grem1 on MBMSCs osteogenic differentiation. Results: Grem1 expression was significantly elevated in the MBMSCs and mandibular tissues of POP rats, accompanied by inhibited osteogenic differentiation. Grem1 levels were inversely proportional to osteogenic capacity and BMP/Smad1/5 signaling activity. BMP-2 alleviated Grem1's inhibitory effects on the BMP/Smad1/5 pathway, influencing MBMSCs' osteogenic differentiation. Upregulating Grem1 in MBMSCs suppressed BMP/Smad1/5 pathway activity and osteogenic differentiation, while Grem1 knockdown restored these processes in the OVX group. Conclusion: Grem1 reduces osteogenic capacity in mandibular POP rats by inhibiting the BMP/Smad1/5 signaling pathway. Targeting Grem1 or enhancing BMP/Smad1/5 signaling activity may improve mandibular bone health in osteoporosis patients. (c) 2025 The Author(s). Published by Elsevier BV on behalf of The Japanese Society for Regenerative Medicine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).