Nanoparticles of naturally occurring PPAR-γ inhibitor betulinic acid ameliorates bone marrow adiposity and pathological bone loss in ovariectomized rats via Wnt/β-catenin pathway

• DOI: 10.1016/j.lfs.2022.121020
• Publication Date: 2022-09-30T16:23:59Z
• Authors: Anirban Sardar; Shalini Gautam; Shradha Sinha; Divya Rai; Ashish Kumar Trip...; Geeta Dhaniya; Prabhat Ranjan Mi...; Ritu Trivedi
• Keywords: 0303 health sciences; Ovariectomy; Core Binding Factor Alpha 1 Subunit; Cell Differentiation; Estrogens; Rats; 3. Good health; PPAR gamma; 03 medical and health sciences; Bone Marrow; Osteogenesis; Humans; Animals; Osteoporosis; Nanoparticles; Female; Obesity; Betulinic Acid; Wnt Signaling Pathway; beta Catenin; Adiposity

Postmenopausal osteoporosis is one of the world's biggest yet unnoticed health issues. After ovariectomy, declined estrogen level significantly contributes to the elevation of bone marrow adiposity and bone loss leading to osteoporosis. Therapeutics to prevent osteoporosis addressing various aspects are now in short supply. In this study we made an approach to synthesize nanoparticles of naturally occurring PPAR-γ inhibitor, betulinic acid (BA/NPs) and tested the same in altered bone metabolisms developed after ovariectomy.The osteogenic efficacy of BA/NPs was established in human and rat primary osteoblast cells using qRT-PCR and immunoblot analysis. Furthermore, lineage allocations of multipotent bone marrow stromal cells were evaluated. Various aspects of altered bone metabolism after ovariectomy such as bone marrow adiposity and pathological bone loss were evaluated using μCT and histological assessments.BA/NPs exert potential osteogenic efficacy by modulating key osteogenic markers such as RUNX2 and BMP2. Mechanistically BA/NPs regulate osteoblastogenesis through Wnt/β-catenin signaling. Further, BA/NPs showed the potential to inhibit the differentiation of multipotent BMSCs towards adipogenesis while favouring the osteogenic lineage via Wnt/β-catenin pathway. In the in vivo study, increased bone marrow adiposity was reduced in ovariectomized rats after BA/NPs treatment as assessed by histology and μCT analysis. Loss of bone mineral density as a hallmark of pathological bone loss was also abrogated by BA/NPs. Furthermore, increased obesity after OVX was also prevented in BA/NPs treated animals.Our findings imply that BA/NPs could be used further as a viable drug lead to counteract various pathophysiological challenges after menopause.