Curcumin inhibits osteoclastogenesis by reducing osteoblast membrane-bound RANKL via MMP14 interaction

Osteoporosis is a debilitating bone disease characterized by excessive osteoclastogenesis, leading to bone loss. Current treatments often target RANKL signaling, a key pathway in osteoclast differentiation. However, the precise mechanisms regulating membrane-bound RANKL (mRANKL) on osteoblasts, which plays a more prominent role than soluble RANKL (sRANKL), remain underexplored. Understanding these mechanisms could unlock novel therapeutic strategies for osteoclastic bone disorders.

Researchers investigated curcumin's effect on mRANKL expression in osteoblasts both in vitro and in vivo. In vitro, osteoblasts were treated with curcumin, and mRANKL levels were assessed using FACS. Co-culture experiments involving osteoclast precursors (OCPs) and osteoblasts were used to analyze curcumin's indirect inhibition of osteoclast differentiation. In vivo, Tg-hRANKL transgenic mice were utilized to study curcumin's impact on upregulated RANKL levels. Finally, the involvement of MMP14 in curcumin-mediated mRANKL regulation was explored, including MMP14 silencing experiments.

Curcumin significantly reduced mRANKL expression in osteoblasts. In Tg-hRANKL transgenic mice, curcumin abrogated the upregulated RANKL levels in osteoblasts. Additionally, curcumin increased MMP14 expression in osteoblasts and enhanced the MMP14-RANKL interaction.

Co-culture assays demonstrated that curcumin exerted the weakest inhibitory effect on osteoclast differentiation when OCPs were co-cultured with mRANKL-negative osteoblasts, highlighting mRANKL's critical role. Importantly, silencing MMP14 in osteoblasts reversed curcumin-inhibited mRANKL levels and osteoclast differentiation, confirming MMP14's essential role in this mechanism.