It is demonstrated that vitamin D prevents bone loss through the coordinated regulation of immune and gut homeostasis, reconciling its apparent pro-resorptive effects in vitro with its overall anti-resorptive outcomes in vivo.
Abstract
Osteoporosis is a prevalent skeletal disorder characterized by deterioration of bone microarchitecture and loss of bone mineral density, leading to increased fracture risk and substantial health and economic burdens, particularly among older adults. Bone remodeling is orchestrated by a complex interplay of systemic and local regulators, among which vitamin D plays a central role in maintaining skeletal homeostasis. Although numerous studies have examined the effects of vitamin D on bone metabolism, outcomes have been inconsistent across populations, dosing regimens, and experimental models. To clarify the net skeletal impact of vitamin D, we investigated its effects in postmenopausal osteoporosis (PMO). Vitamin D (1,25-dihydroxyvitamin D3– active form of vitamin D) supplementation effectively prevented bone loss in ovariectomized mice, at both lower and higher concentrations. Mechanistically, vitamin D promoted osteoclast differentiation in vitro, consistent with its RANKL-dependent pro-osteoclastogenic activity, yet paradoxically conferred bone protection in vivo. This discrepancy was explained by vitamin D’s profound immunomodulatory effects, which reshaped both innate and adaptive immune responses to suppress osteoclast formation and function. Concurrently, vitamin D improved intestinal barrier integrity and restored gut microbial composition, thereby stabilizing the gut-immune-bone axis and reducing pro-resorptive inflammatory signaling. Together, these findings demonstrate that vitamin D prevents bone loss through the coordinated regulation of immune and gut homeostasis, reconciling its apparent pro-resorptive effects in vitro with its overall anti-resorptive outcomes in vivo. This integrated mechanism highlights immune-gut microbial modulation as a key mediator of vitamin D-induced bone preservation and supports the development of vitamin D as an immunotherapeutic adjunct for the prevention and management of PMO. Altogether, our findings for the first time dissect the paradox surrounding the osteoprotective property of vitamin D supplementation. Graphical Abstract: Vitamin D strengthens intestinal barrier integrity and restores gut microbial composition, which stabilizes the gut-bone axis and suppresses pro-resorptive inflammatory signaling. Vitamin D enhances osteoclastogenesis both directly and through ILC3– and Th17-mediated pathways, while inhibiting osteoclastogenesis via Treg– and Breg-dependent mechanisms. In circulation, vitamin D maintains the homeostasis between IL-10 and IL-17 cytokines. Collectively, these results indicate that vitamin D helps prevent bone loss by orchestrating the immune system and maintaining gut homeostasis.
Introduction. Osteoporosis is a systemic metabolic skeletal disease in which decreased bone mineral density, impaired microarchitecture and in-creased fracture risk are associated not only with calcium and vitamin D deficiency, but also with dysregulation of calcium-phosphate metabolism, hormonal deficiency, lipid abnormalities, chronic inflammation, oxidative stress and impaired coupling between osteoclastic and osteoblastic phases of bone remodeling. From the perspective of medicinal chemistry, hydroxyapatite structure, calcium and phosphate metabolism, parathyroid hormone, vitamin D, FGF23, RANK/RANKL/OPG balance, Wnt/β-catenin signaling, PPARγ-dependent adipogenic differentiation of mesenchymal stromal cells, lipid peroxidation and antioxidant systems are of particular importance. Objective – to summarize current data on the relationship between calcium homeostasis, lipid profile, and oxidative stress in osteoporosis, with a focus on the medical-chemical mechanisms of bone remodeling, biological incorporation of calcium into the bone matrix, bone-vascular comorbidity, and potential laboratory targets for further research. Main points. Bone tissue is a dynamic mineralized system in which hydroxyapatite crystals interact with collagen matrix, osteoblasts, osteoclasts, osteocytes and the vascular microenvironment. Calcium homeostasis is regulated by vitamin D, parathyroid hormone, calcitonin, FGF23, renal han-dling, and intestinal absorption; it is essential to distinguish between calcium intake, calcium bioavailability, and its incorporation into the mineralized matrix. Lipid profile affects osteogenesis via PPARγ, Wnt/β-catenin, cytokines and oxidized lipoproteins. Oxidative stress disrupts remodeling through osteoblast damage, RANKL/OPG imbalance, RUNX2 suppression and lipid peroxidation. Conclusion. Osteoporosis should be considered as a systemic disorder of mineral, lipid, hormonal and redox metabolism. A comprehensive laborato-ry panel including calcium, phosphate, 25(OH)D, parathyroid hormone, FGF23, alkaline phosphatase, P1NP, β-CTX, lipid profile, oxidized lipoproteins, malondialdehyde, 4-hydroxynonenal, GSH/GSSG, superoxide dismutase, catalase, glutathione peroxidase, hsCRP, IL-6, TNF-α, osteocalcin, osteoprotegerin, RANKL, and sclerostin may be promising for a personalized approach to patient assess-ment and further research.
M. Khabibulina, A. Morozov, M. Shamilov et al.· Problems of Biological Medic...· 0 citations
Osteoporosis is a systemic skeletal disease characterized by low bone mass, deterioration of bone microarchitecture, and increased fracture risk, which imposes a heavy burden on global public health, especially in postmenopausal women and the elderly. The gut-bone axis, a bidirectional regulatory network between the gut microbiota and bone metabolism, has emerged as a novel therapeutic target for osteoporosis. Indole derivatives, a class of bioactive compounds derived from tryptophan metabolism by gut microbiota or plant secondary metabolism, have attracted increasing attention due to their extensive biological activities, including anti-inflammatory, antioxidant, and metabolic regulatory effects. Accumulating evidence indicates that indole derivatives can regulate bone homeostasis through the gut-bone axis, providing a new strategy for the prevention and treatment of osteoporosis. This review systematically summarizes the types of indole derivative, elaborates their molecular mechanisms in the treatment of osteoporosis via the gut-bone axis (including regulating gut microbiota composition, maintaining intestinal barrier integrity, modulating immune-inflammatory responses, and mediating key signaling pathways), and discusses the current translational progress, existing challenges, and future prospects. This review aims to provide a comprehensive theoretical basis for the clinical application of indole derivatives in osteoporosis treatment and the development of novel targeted drugs.
Wendong Wang· Frontiers in Cellular and In...· 0 citations
Osteoporosis is a systemic metabolic bone disease characterized by decreased bone mass, destruction of bone microstructure, and increased risk of fractures. Traditional views mainly attribute it to an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, but increasing evidence suggests that the pathogenesis and progression of osteoporosis are also regulated by complex interactions among the nervous system, immune system, and skeletal system. The neuro-immune-bone axis provides an important framework for integrating the bidirectional regulation between innervation, immune microenvironment, and bone remodeling process. This article systematically reviews the basis of interactions among sensory nerves, sympathetic nerves, immune cells, and bone cells in bone homeostasis, with a focus on the roles of sympathetic nerve activation, sensory neuropeptide imbalance, and immune inflammatory remodeling in the progression of osteoporosis. Furthermore, this article compares the differential imbalance patterns of this axis in postmenopausal osteoporosis, age-related osteoporosis, and secondary osteoporosis, and accordingly discusses its potential significance for disease classification and risk identification. At the therapeutic level, this article further distinguishes between clinically well-established management strategies and mechanistic interventions still in the exploratory stage. The former includes guideline-recommended anti-osteoporosis drugs, exercise, nutritional support, fall prevention, and control of primary diseases; the latter includes strategies such as sympathetic nerve regulation, CGRP-related interventions, Treg/Th17 balance regulation, and macrophage polarization, which are currently mainly based on animal experiments, mechanistic studies, observational evidence, or early translational research and cannot yet be considered routine clinical treatment. Therefore, the neuro-immune-bone axis is currently more suitable as a theoretical framework to explain the heterogeneity of osteoporosis and guide mechanistic research, and its practical value in precise classification, treatment selection, and clinical decision-making still requires further validation through prospective cohort and intervention trials. By integrating existing evidence, this article aims to offer a theoretical foundation for understanding the multi-system interaction mechanisms of osteoporosis, establishing an evidence stratification framework, and exploring future individualized interventions.
Yupeng Zhang, Junchen Lu, Guojun Deng et al.· Frontiers in Immunology· 0 citations
Results indicate that radiofrequency echographic multispectrometry provides BMD and fracture risk assessment comparable to DXA in patients on peritoneal dialysis, while also highlighting the impact of vascular calcifications on the diagnostic accuracy of lumbar spine DXA measurements.
O. Nishkumay, O. Iaremenko, V.E. Kondratiuk et al.· International Journal of End...· 0 citations
Osteoporosis is a systemic skeletal disease characterized by progressive bone loss and an increased risk of fracture, and it represents a major public health challenge worldwide. Osteoporosis has multiple pathogenic determinants, including age, endocrine disorders and medication. Current therapeutic approaches primarily aim to promote osteogenesis directly or inhibit osteoclast activity; however, these strategies may limit therapeutic efficacy and increase the risk of adverse effects. The present review provided an integrated perspective on the pathogenesis of osteoporosis from the standpoint of glucose metabolism. Glucose oxidation generates ATP and metabolic intermediates that are key to bone homeostasis. During early differentiation, mesenchymal stem cells rely predominantly on glycolysis during commitment toward pre-osteoblasts, whereas maturation into functional osteoblasts depends more notably on oxidative phosphorylation. The fusion and differentiation of osteoclasts require robust mitochondrial oxidation. Lactate derived from anaerobic metabolism has a dual role in bone metabolism. High-risk populations for osteoporosis include postmenopausal women, patients with type 2 diabetes mellitus and individuals with obesity. Estrogen exerts anti-inflammatory and antioxidant effects through receptor activation. Excessive production of advanced glycation end-products disrupts the bone matrix, whereas hyperlipidemia promotes inflammatory factor-induced bone resorption. These pathological changes disrupt the insulin receptor substrate/PI3K/AKT signaling pathway, compromise glucose transporter-mediated cellular glucose uptake and thus, contribute to relative insulin resistance and insufficiency compared with physiological states. In conclusion, the present review demonstrated that abnormal glucose metabolism is a key pathogenic mechanism in osteoporosis and that targeting insulin signaling may represent a fundamental strategy for correcting glucose metabolic abnormalities across diverse etiologies.
Sheng-Yao Peng, Z. Yao, Junzhe Guo et al.· International Journal of Mol...· 0 citations
OBJECTIVE
Osteoporosis is associated with reduced active vitamin D, but the molecular basis remains incompletely understood. This study investigated how active vitamin D preserves skeletal homeostasis and prevents bone loss.
DESIGN
Experimental mechanistic study using genetically modified mouse models and bone marrow mesenchymal stem cells (BMSCs).
METHODS
Mice with reduced active vitamin D production were examined for bone mass, skeletal ageing, and osteogenic capacity. Mouse and human BMSCs were used to assess proliferation, osteogenic differentiation, and molecular signalling. Gene expression, protein turnover, and pathway analyses determined how active vitamin D regulates cell-cycle control in skeletal progenitors. Genetic deletion studies tested the functional contribution of P27 to bone loss.
RESULTS
Active vitamin D protected against osteoporosis by activating a vitamin D receptor (VDR)-dependent pathway that increased cyclin-dependent kinase 2 (CDK2) expression and promoted P27 degradation in BMSCs. Loss of this signalling caused P27 accumulation, reduced stem-cell proliferation, impaired osteogenic differentiation, and enhanced skeletal senescence, leading to bone loss. Active vitamin D promoted P27 phosphorylation at threonine 187 and its degradation via the ubiquitin-proteasome pathway. Importantly, P27 deletion partially rescued the osteoporotic phenotype in mice with reduced active vitamin D production.
CONCLUSIONS
Active vitamin D maintains bone integrity through a VDR-dependent mechanism that enhances CDK2 expression and promotes P27 degradation in BMSCs. These findings identify a previously unrecognised mechanism linking vitamin D signalling to skeletal ageing and suggest that targeting P27 turnover may offer a therapeutic strategy, provided tissue-specific approaches mitigate the oncogenic risks of P27 manipulation.
Fangrong Xu, Quan Liu, Mingxin Huang et al.· European Journal of Endocrin...· 0 citations