Mechanism of BMP2 induced differentiation of bone marrow mesenchymal stem cells into adipocytes

Date
2024
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Bone morphogenetic protein 2 (BMP2) is a crucial regulator of stem cell differentiation, influencing the fate of bone marrow-derived stem cells (BMSCs). While BMP2 is traditionally known for promoting osteogenesis, emerging evidence suggests its significant role in adipogenesis, leading to the accumulation of fat cells within the bone marrow. Mesenchymal stem cell differentiation into adipocytes relies on Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) activation. The level of adipocyte differentiation within the bone marrow affects osteoblast differentiation, as both cell types are derived from the same mesenchymal lineage. Osteoblasts are responsible for bone formation, and a reduced number of osteoblasts leads to decreased bone mass and conditions such as osteoporosis. Osteoporotic patients typically exhibit a high level of BMP2, accompanied by increased adipocytes and decreased osteoblasts in their bone marrow. ☐ BMP2, due to its osteo-inductive ability, has been explored as a therapeutic agent for osteoporosis. However, the dual role of BMP2 in promoting the differentiation of MSCs into both osteoblasts and adipocytes poses significant challenges to its efficacy as a treatment for osteoporosis. BMP2 signaling is a complex process that occurs through BMP Receptor Type Ia (BMPRIa) and BMP Receptor Type II (BMPRII). High BMP2 levels at 200 nM result in BMPRIa cleavage, but the downstream effects and factors determining whether osteogenesis or adipogenesis will occur remain unclear. This study investigates the mechanisms underlying BMP2-induced differentiation of BMSCs into adipocytes, focusing on BMP2-induced BMPRIa cleavage and its impact on PPARγ expression. ☐ Immortalized murine myoblasts (C2C12 cells) and primary BMSCs from mice of different ages were treated with varying BMP2 concentrations. High BMP2 levels (200 nM) significantly increased PPARγ expression and led to nuclear accumulation of BMPRIa, as observed via immunofluorescence staining. Western blot analyses confirmed BMPRIa cleavage and identified a cleavage fragment with a molecular weight corresponding to a Caspase1 cleavage fragment in cells treated with 200 nM BMP2. In primary BMSCs, Caspase1 inhibition abolished this cleavage band, highlighting Caspase1's involvement. Furthermore, Caspase1 inhibition also prevented BMPRIa's nuclear accumulation and reduced PPARγ expression, confirming Caspase1's role in BMPRIa cleavage. In contrast, BMSCs from 15-month-old mice showed no significant nuclear accumulation of BMPRIa or changes in PPARγ expression across BMP2 treatments, indicating age-related impairment in BMP2 signaling and receptor processing. ☐ This study reveals that Caspase1-mediated BMPRIa cleavage drives adipogenesis in primary bone marrow stromal cells through nuclear interactions. Understanding these molecular mechanisms enhances comprehension of adipogenesis within the bone marrow and offers potential therapeutic avenues for modulating treatment with BMP2 in low bone mineral density and osteoporosis.
Description
Keywords
Adipogenesis, Bone morphogenetic protein 2, Bone marrow mesenchymal stem cells, Osteoporosis, Stem cell differentiation
Citation