The Mechanism of Icariin in Regulating BMSCs for Treating Osteoporosis: A Review.

introductionOsteoporosis (OP) is a common skeletal disease mainly caused by the imbalance between bone formation and bone resorption. Dysfunction and senescence of bone marrow mesenchymal stem cells (BMSCs) are critical pathogenic factors for OP, resulting in impaired osteogenic differentiation, increased adipogenic shift, and enhanced susceptibility to inflammation and oxidative stress. Therefore, the purpose of this review is to systematically synthesize current evidence on how Icariin (ICA)-a major bioactive flavonoid from

methodsThis narrative review systematically synthesized preclinical and mechanistic evidence regarding Icariin-mediated regulation of BMSC function in osteoporosis. Relevant cellular, animal, pharmacological, and mechanistic studies were reviewed, with emphasis on BMSC senescence, osteogenic/ adipogenic lineage commitment, oxidative stress, inflammation, and major signaling pathways, including Wnt/β-catenin, Notch, BMP/Runx2/Osx, MAPK, and OPG/RANK/RANKL.

resultsICA can promote osteogenic differentiation and inhibit osteoclastogenesis by regulating multiple signaling pathways simultaneously. ICA activates the Wnt/β-catenin pathway to enhance the stability of β-catenin and its downstream transcriptional programs, modulates Notch signaling through regulating the activity of DLL1, Jagged1, and NICD, and promotes the BMP/Runx2/Osx axis, which favors osteoblast lineage commitment. Additionally, it controls the activity of MAPK (ERK, p38, JNK) and restores bone homeostasis by managing the OPG/RANK/RANKL system, leading to reduced osteoclastogenesis and decreased production of inflammatory cytokines. In addition to regulating lineage commitment, ICA alleviates BMSC senescence by reducing oxidative stress, DNA damage, mitochondrial dysfunction, and SASP-associated microenvironmental deterioration. DISCUSSION: Collectively, these effects promote osteogenesis, maintain stem cell vitality, and mitigate OP-induced bone loss. The hierarchy, crosstalk, and cell-type specificity of ICA-targeted signaling networks require further elucidation to facilitate clinical translation.

conclusionPreclinical evidence suggests ICA is a promising natural compound with the potential to mitigate OP progression by comprehensively regulating BMSC functions and bone remodeling pathways. Future research needs to focus on rigorous clinical trials and single-cell-level studies to determine the specific BMSC subpopulations responsive to ICA and optimize its therapeutic application.