Sildenafil suppresses osteoporosis-related bone marrow adiposity by inhibiting Adipogenic differentiation of mesenchymal stem cells
Abstract
Background: Within the bone marrow niche, maintaining equilibrium between mesenchymal stem cell (MSC) commitment toward osteoblasts and adipocytes is essential for preserving tissue homeostasis. Excessive adipogenic differentiation of MSCs contributes to disorders such as osteoporosis. Targeting marrow adiposity, alongside promoting osteogenesis, may offer a promising therapeutic approach. Sildenafil, a U.S. Food and Drug Administration-approved drug, has been suggested to influence cellular differentiation; however, its potential role in regulating adipogenic differentiation of MSCs remains unclear. Here, we investigated its regulatory effects on MSC adipogenic conversion and bone marrow fat accumulation under osteoporotic conditions, as well as its underlying mechanisms.
Methods: Adipogenic differentiation of human MSCs (hMSCs)-specifically human adipose-derived MSCs (hASCs) and human bone marrow-derived MSCs (hBMSCs)-was assessed by Oil Red O staining, quantitative reverse transcription polymerase chain reaction, and immunofluorescence. In vivo effects were evaluated using an ectopic adipogenesis model in nude mice and two osteoporotic mouse models (ovariectomized and tail-suspension models). RNA sequencing was performed for mechanistic analysis, followed by experimental validation.
Results: Sildenafil significantly inhibited adipogenic differentiation of hMSCs in vitro, suppressed adipogenesis of hBMSCs in vivo, and reduced bone marrow adiposity in osteoporotic mice. The…
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