Reuterin drives osteogenic and suppresses adipogenic differentiation of bone marrow mesenchymal stem cells via BMP/SMAD signaling to ameliorate osteoporosis.

Osteoporosis, a prevalent skeletal condition defined by diminished bone density and disrupted microarchitecture, dramatically elevates fracture risk. Its pathophysiology is now understood to extend beyond classic remodeling imbalances to include a pivotal shift in bone marrow mesenchymal stem cell (BMSC) differentiation, where adipogenesis is favored over osteogenesis-a key feature of aging and estrogen deficiency. The emerging "gut-bone axis" suggests that microbiota-derived metabolites can systemically influence skeletal homeostasis, presenting new therapeutic possibilities. This research uncovers the direct osteoanabolic and anti-adipogenic properties of Reuterin (3-hydroxypropionaldehyde, Reut), a principal antimicrobial metabolite from Lactobacillus reuteri. In vitro, Reut (5-20 μM) showed excellent cytocompatibility, dose-dependently boosting osteogenic differentiation (increased ALP activity and mineralization) while effectively suppressing adipogenic differentiation (decreased lipid accumulation) in BMSCs. Mechanistically, Reut specifically activated the canonical BMP-Smad pathway, demonstrated by the rapid phosphorylation and nuclear translocation of Smad1/5/9 and the upregulated expression of its direct targets (ID1, ID2). This activation was crucial, as the BMP receptor inhibitor LDN-193189 completely negated Reut's effects. In an ovariectomized (OVX) rat model, systemic Reut administration (10 mg/kg, every other day for 8 weeks) not only mitigated trabecular bone loss and enhanced biomechanical properties but also markedly reversed the OVX-induced expansion of marrow adipose tissue (MAT). Remarkably, the bone-preserving efficacy of Reut was statistically equivalent to that of teriparatide (TPTD), a clinically approved anabolic agent, while both treatments similarly and significantly countered the pathological marrow adiposity. These results establish Reut as a novel, gut microbiome-derived therapeutic metabolite that rectifies the fundamental lineage imbalance in osteoporosis by directly engaging the BMP-Smad pathway, offering a distinct postbiotic strategy for anabolic bone therapy.