Sodium hydrosulfide alleviates osteoporosis by suppressing osteoclastogenesis via the inhibition of the NF-κB signaling

Background: While current pharmacotherapies for osteoporosis (OP) such as bisphosphonates reduce fracture risk, their long-term use is limited by adverse effects including gastrointestinal toxicity, osteonecrosis of the jaw, and atypical femoral fractures. Hydrogen sulfide (H₂S), an endogenous gasotransmitter with anti-inflammatory properties, emerges as a potential alternative, but the role of its donor sodium hydrosulfide (NaHS) in osteoporosis remains unexplored. This study investigates NaHS-driven bone-protective mechanisms, emphasizing its ability to modulate the NF-κB/IκB-α axis—a pathway critical in osteoclastogenesis. Methods: Sham controls (n=6) and Ovariectomized (OVX) mice (osteoporosis model; 4 groups, n=6) received NaHS (0, 0.38, 0.75, 1.5 mg/kg/day) or vehicle for 4 weeks. Bone mineral density (BMD) was quantified by Micro-CT. Osteoclast differentiation was assessed in bone marrow-derived macrophages (BMMs) and RAW264.7 cells via TRAP staining. Molecular mechanisms were deciphered using ubiquitination assays, nuclear/cytoplasmic fractionation, and immunofluorescence. Results: NaHS treatment increased lumbar BMD and trabecular bone volume/tissue volume in OVX mice compared to untreated controls. In vitro, NaHS (0.15mM) suppressed RANKL-induced osteoclastogenesis (p<0.05). Mechanistically, NaHS was shown for the first time to stabilize IκB-α by inhibiting its ubiquitination, thereby blocking NF-κB p65 nuclear translocation. Conclusions: NaHS mitigates OVX-induced bone loss via dual inhibition of osteoclast differentiation (through IκB-α/NF-κB blockade) and bone resorption. Its capacity to circumvent the limitations of current therapies positions NaHS as a novel candidate for osteoporosis management.