Sildenafil suppresses osteoporosis-related bone marrow adiposity by inhibiting Adipogenic differentiation of mesenchymal stem cells.

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 results demonstrated that 10 mg/L exerted the most pronounced inhibitory effect on lipid accumulation. Mechanistically, these effects may occur through suppression of the PI3K-AKT signaling pathway.

CONCLUSIONS

Sildenafil inhibited adipogenic differentiation of hMSCs and reduced osteoporosis-related bone marrow adiposity, highlighting its therapeutic potential for marrow adiposity associated with osteoporosis and other conditions characterized by excessive MSC adipogenesis.