Naringin also inhibits osteoclastogenesis by both modifying RANKRANKL interactions and inducing apoptosis in osteoclasts in vitro.In addition, naringin acts on the estrogen receptor in bone to mimic the native bonepreserving effects of estrogen, with few systemic side effects on other estrogensensitive tissues.The efficacy of naringin therapy in reducing the osteolysis characteristic of common musculoskeletal pathologies such as osteoporosis, degenerative joint disease, and osteomyelitis, as well as inflammatory conditions affecting bone such as diabetes mellitus, has been extensively demonstrated in vitro and in animal models.Naringin thus represents a naturally abundant, costefficient agent whose potential for use in novel musculoskeletal biotherapies warrants revisiting and further exploration through human studies.Here, we review the cellular mechanisms of action that have been elucidated regarding the action of naringin on bone resident cells and the bone microenvironment, in vivo evidence of naringins osteostimulative and chondroprotective properties in the setting of osteolytic bone disease, and current limitations in the development of naringincontaining translational therapies for common musculoskeletal conditions.Flavonoids are phenolic compounds widely distributed among vascular plants; there are approximately known natural products within the flavonoid family.We also briefly describe translational research and pharmacologic challenges that must be overcome to successfully harness the bonepromotingpreserving effects of naringin.Naringin enhances the production of cell survival proteins and reduces the expression of genes involved in the inflammatory response.In the musculoskeletal system, bone morphogenetic proteins have been shown to be important in skeletogenesis, limb and digit formation, and fracture repair.BMP is responsible for the differentiation of multipotent stem cells to an osteoblastlike lineage.This osteoblastic differentiation yields increased bone formation, with clinical potential to restore bone mineral density in osteopenia and osteoporosis and enhance fracture healing.Indeed, primary osteoblasts cultured with naringin displayed increased BMP protein and mRNA levels.Osteoblast activity increased in the presence of naringin in UMR cells, as demonstrated by the colorimetric tetrazolium assay, which evaluates cellular viability, metabolism, and proliferation via oxidoreductases, and increased total protein and alkaline phosphatase activity.Naringin has been shown to decrease osteoclastogenesis and thus osteolysis in osteoclastic pathologies, such as osteoporosis in menopause and diabetic osteoporosis.Naringin decreases osteoclastogenesis by inhibiting RANK RANKL interaction by inducing expression of the receptor decoy OPG as well as directly decreasing expression of osteoclastic genes.Physiological levels of estrogen maintain bone stock in females by inducing osteoclast apoptosis and decreasing inflammatory cytokines that are osteoclastogenic; therefore, the loss of estrogen results in osteoporosis due to increased osteoclastogenesis.Naringin also decreases the inflammatory cytokines IL, IL, and TNF that stimulate osteoclastogenesis.Moreover, it has been established that the extracellular signalregulated kinase MAPK pathway plays a vital role in osteoblastic differentiation.Naringin doses of gml demonstrated the greatest proosteogenic effects upon rat bone marrowderived mesenchymal stem cells, which persisted for days.The proosteogenic potential of naringin may be harnessed or enhanced through novel formulations and drug delivering biomaterial constructs.The application of naringinloaded polymeric micelles to human adiposederived stem cells yielded greater osteogenic differentiation, as characterized by increased osteopontin expression and bony matrix mineralization, than was observed in the presence of free naringin.Naringin additionally enhances osteoblast survival by increasing, dihydroxyvitamin D signaling in osteoblasts in vitro.