These findings suggest that naringin is a potent natural promoter of osteogenesis with the potential for use in stem cell therapies, which traditionally use dexamethasone for lineage differentiation.Such treatments are often limited by adipogenesis secondary to glucocorticoid exposure, even when conducted in osteogenic media.Increased osteoclastogenesis is the hallmark of many bone pathologies, including senile osteoporosis due to increased adipogenesis, postmenopausal osteoporosis secondary to the loss of the Targetmol's CORM3,132 osteoblastic and antiosteoclastic effects of estrogen, and diabetic osteoporosis induced by the proinflammatory state and resultant macroangiopathies and microangiopathies characteristic of diabetes mellitus.Osteoclastogenesis is mediated by interactions between RANKRANKL and osteoprotegrin; pathologic states increase the RANKRANKL ratio present in bone and decrease production of OPG.Naringin has been shown to successfully disrupt osteoclastogenesis via the RANKRANKL pathway. Furthermore, naringin enhances OPG release from osteoblasts, reducing interactions between RANKL and its receptor and preventing osteoclast differentiation.The combination of these mechanisms suppresses the expression of genes critical to osteoclast development.In childhood and adolescence, estrogen drives progression to skeletal maturity and the maturation and fusion of the epiphyseal growth plates.In adults, estrogen maintains bone stock and influences bone turnover by inhibiting bone resorption.Estrogen mediates its boneprotective effects through estrogen receptor. Estrogen also induces apoptosis in osteoclasts by upregulating interactions between the death receptor and its ligand. Furthermore, estrogen inhibits osteoblastmediated osteoclastogenesis by decreasing the production of IL, IL, and TNF, which induce osteoclast differentiation from progenitor cells.Estrogen also modulates the synthesis of OPG, which serves as a decoy receptor for RANKL, by osteoblasts, thus hindering osteoclastogenesis.The loss of estrogen production in menopause is the primary causative factor of diminished BMD and increased predisposition to fractures among postmenopausal women.Naringin also downregulates expression of BCL while upregulating expression of BAX, caspase, and cytochrome C, suggesting that naringin may induce osteoclast apoptosis through regulation of the mitochondrial apoptosis pathway.The ability of naringin to induce apoptosis in exposed osteoclasts and upregulate OPG mRNA levels in MCTE cells hinders osteoclastogenesis in ways that mirror the native effects of estrogen on bone.By targeting pathways vital to the pathogenesis of menopauseinduced bone loss, naringin may stem the musculoskeletal consequences of reduced estrogen production for the restoration of bone stock.Daily oral naringin administration increased femoral bone mass in healthy mice by enhancing trabecular and cortical bone content and quality. The majority of osteoporosis animal models have employed ovariectomy to reduce circulating estrogen levels and induce osteoclastmediated bone resorption.This model simulates the loss of estrogen production characteristic of menopause, after which the cortical and trabecular BMD and interconnections between bone cells become drastically diminished and the risk of pathologic fracture significantly increases, resulting in osteopenia and osteoporosis. Orchidectomized, retinoic acidinduced, and disuseinduced animal models of osteoporosis have also been generated to study disease physiology and therapeutic avenues.Naringin has been found to mitigate the loss of bone calcium and phosphorus content, BMD, bone architecture quality and bone mechanical strength across all murine models of osteoporosis, particularly in OVX mice and rats. In vivo effects of naringin.Osteoporosis secondary to the loss of estrogens anabolic effects during menopause, the proinflammatory state of diabetes that promotes osteoclastogenesis, or the loss of pERK due to glucocorticoid use leads to decreased trabeculae volume, yielding an increased risk of fracture.