BACKGROUND:Osteoporosis is a prevalent bone disease that increases frailty. Developing a nomogram prediction model to predict osteoporosis risk at multiple time points using bone mineral densities, behavioral habits, and clinical risk factors would be essential to identify individual risk and guide prevention. METHODS:The study population from the UK Biobank was followed from 2014 to December 31st, 2022. The study outcome was identified as the first occurrence of osteoporosis in the UK Biobank during the follow-up period. After rebalancing with the synthetic minority over-sampling technique, a nomogram prediction model was developed using a LASSO Cox regression. Model discrimination between different risk levels was visualised with Kaplan-Meier curves, and model performance was evaluated with integrated c-index, time-dependent AUC, calibration curves and decision curve analysis (DCA). RESULTS:The model identified several risk factors for osteoporosis, including higher age, underweight, and various clinical risk factors (such as menopause, lower hand grip strength, lower bone mineral density, fracture history within 5 years, and a history of chronic disease including hypercholesterolemia, cardiovascular disease, bone disease, arthritis, and cancer). Kaplan-Meier curves showed that risk levels predicted by the nomogram model were significantly distinct. The c-indexes were 0.844 and 0.823 for training and validation datasets, respectively. Time-dependent AUC, calibration curves and DCA indicated good discrimination, model fit and clinical utility, respectively. CONCLUSIONS:The nomogram model could properly quantify the five-year risk of osteoporosis and identify high-risk individuals. This might effectively reduce the burden of osteoporosis on the population.

BACKGROUND:Ankylosing spondylitis (AS) is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints, alongside abnormal bone growth. In previous studies, we reported that mesenchymal stem cells (MSCs) derived from individuals with AS demonstrated a remarkable inhibition in the formation of osteoclasts compared to those obtained from healthy donors. The mechanism through which MSCs from AS patients achieve this inhibition remains unclear. AIM:To investigate the potential underlying mechanism by which MSCs from individuals with ankylosing spondylitis (AS-MSCs) inhibit osteoclastogenesis. METHODS:We analysed fat mass and obesity-associated (FTO) protein levels in AS-MSCs and MSCs from healthy donors and investigated the effects and mechanism by which FTO in MSCs inhibits osteoclastogenesis by coculturing and measuring the levels of tartrate-resistant acid phosphatase, nuclear factor of activated T cells 1 and cathepsin K. RESULTS:We found that FTO, an enzyme responsible for removing methyl groups from RNA, was more abundantly expressed in MSCs from AS patients than in those from healthy donors. Reducing FTO levels was shown to diminish the capacity of MSCs to inhibit osteoclast development. Further experimental results revealed that FTO affects the stability of the long non-coding RNA activated by DNA damage (NORAD) by altering its N6-methyladenosine methylation status. Deactivating NORAD in MSCs significantly increased osteoclast formation by affecting miR-4284, which could regulate the MSC-mediated inhibition of osteoclastogenesis reported in our previous research. CONCLUSION:This study revealed elevated FTO levels in AS-MSCs and found that FTO regulated the ability of AS-MSCs to inhibit osteoclast formation through the long noncoding RNA NORAD/miR-4284 axis.

The widespread use of human mesenchymal stem cells(hMSCs) is impeded by functional loss during prolonged expansion. Although multiple approaches have been attempted to preserve hMSCs stemness, a suitable culture system remains to be modified. The interaction between electrical signals and stem cells is expected to better maintain the function of stem cells. However, it remains unclear whether the surface potential of substrates has the potential to preserve stem cell function during in vitro expansion. In our study, hMSCs cultured on materials with different surface potentials could be induced into a reversible quiescent state, and we demonstrated that quiescent hMSCs could be reactivated and transitioned back into the proliferation cell cycle. hMSCs cultured under appropriate potential displayed superior differentiation and proliferation abilities within the same generation compared to conventional conditions. These findings underscore the importance of surface potential as a critical physical factor regulating hMSCs stemness. Manipulating the surface potential of hMSCs culture substrates holds promise for optimising preservation and culture conditions, thereby enhancing their application in tissue repair and regeneration engineering.

OBJECTIVE:Our objective was to investigate the role of neutrophil extracellular traps (NETs) in the pathogenesis of inflammatory disorders in ankylosing spondylitis (AS). METHODS:Local and circulating NETs levels were determined by immunofluorescence (IF) and myeloperoxidase (MPO)-DNA quantification in both patients with AS and AS model SKG mice. Flow cytometry (FCM) was performed to detect the effect of NETs on CD4+ subpopulation differentiation. The therapeutic effects of the neutrophil elastase inhibitor sivelestat (SVT) and the peptidylarginine deiminase 4 (PAD4) inhibitor CI-amidine were evaluated in SKG mice. The localization of NETs and their ability to impede CD4+ Treg cell differentiation were evaluated via IF, FCM, and Western blotting. RNA sequencing and specific inhibitors were used to clarify the detailed mechanism by which NETs inhibit CD4+ Treg differentiation. RESULTS:The NETs levels were elevated locally and systemically in both patients with AS and SKG mice, which impeded the differentiation of CD4+ Treg cells. Blocking NETs formation via SVT or CI-amidine restored the CD4+ Treg ratio and subsequently alleviated inflammation in SKG mice. NETs were internalized by CD4+ T cells, and their associated RNA activated the Toll-like receptor 7 (TLR7)-interferon regulatory factor 7 (IRF-7) axis, which then inhibited Treg differentiation. Inhibiting CD4+ T cells endocytosis, removing the bound RNA component, or blocking the TLR7-IRF-7 axis abrogated the negative effect of NETs on CD4+ Treg differentiation. CONCLUSION:Elevated NETs impeded CD4+ Treg differentiation by activating the TLR7-IRF-7 axis via their associated RNA in AS, and targeting NETs may be a novel treatment strategy for AS and related inflammatory disorders.

Increased adipogenic differentiation and decreased osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) along with slow self-renewal are pivotal causes for decreased bone formation in senile osteoporosis. Circular RNAs (circRNAs) play important roles in cell proliferation and differentiation, and are closely related to osteoporosis. Whether circRNAs orchestrate the adipo-osteogenic balance and the proliferation of BMSCs in osteoporosis remains unclear. We found in this study that circSTX12 was abnormally upregulated in bone sections from osteoporosis patients and in BMSCs from aged mice, as well as in later-generation human BMSCs in culture. Knockdown of circSTX12 in BMSCs resulted in enhanced osteogenesis, decreased adipogenesis, and increased proliferation capacity; circSTX12 overexpression had the opposite effect. RNA pull-down and mass spectrometry revealed the interactions between circSTX12 with CBL and LMO7. At the molecular level, circSTX12 regulated cell fate in BMSCs by competitively binding to CBL, reducing the ubiquitination-mediated degradation of MST1 and thereby activating the Hippo pathway, a key regulator of adipo-osteogenic balance. Knockdown of circSTX12 promoted the nuclear localization of YAP. In addition, our findings suggest that LMO7 mediates circSTX12-induced BMSCs proliferation by regulating the transcription of CCNA2, CCNH, and CCND1. In vivo, injection of antisense oligonucleotides (ASOs) to knockdown circSTX12 promoted bone formation in aged mice. Our results provide evidence for circSTX12 as a regulator of adipo-osteogenic differentiation and proliferation of BMSCs through binding to CBL and LMO7, respectively. Targeting circSTX12 may be a novel approach for osteoporosis treatment.

Rheumatoid arthritis (RA) involves synovial inflammation driven by pathogenic macrophages, whose polarization is regulated by transcription factors (TFs). Interferon regulatory factor 7 (IRF7) is an innate immune regulator, but its role in RA macrophage-mediated inflammation and cartilage destruction remains unclear. This study aimed to define IRF7-dependent regulatory pathways in RA macrophages and evaluate their therapeutic potential. Single-cell RNA sequencing (scRNA-seq) data and SCENIC analysis were used to identify TF-enriched macrophage subpopulations in the RA synovium. Chromatin immunoprecipitation sequencing data (ChIP-seq) were used to map IRF7 binding sites, and bulk RNA-seq data were used to analyse M1 polarization responses. Functional validation included IRF7 knockdown in human monocytes and intra-articular siRNA in a collagen-induced arthritis (CIA) mouse model to assess inflammatory genes, macrophage polarization, and joint pathology. A CD48highS100A12+ proinflammatory macrophage subset was expanded in RA and enriched for IRF7 activity and downstream genes (PTGS2, CXCL10, NF-κB1, and IL-1β). IRF7 directly regulates these genes, and its knockdown reduces M1 polarization and inflammatory gene expression in vitro. In CIA mice, local IRF7 silencing attenuated joint inflammation, synovial hyperplasia, and bone erosion, which correlated with decreased proinflammatory macrophages and increased regulatory T cells. IRF7 appears to promote pathogenic macrophage polarization and inflammatory signaling in RA, and its dysregulation has been associated with disease pathogenesis. Focal IRF7 perturbation can dampen pro-inflammatory networks, suggesting a potentially selective approach for tempering synovial inflammation while limiting systemic immunosuppression. IRF7 is enriched in a CD48highS100A12+ proinflammatory macrophage subset in the RA synovium and directly regulates inflammatory genes (PTGS2, CXCL10, NF-κB1, and IL-1β). Knockdown of IRF7 reduces M1 macrophage polarization and inflammatory gene expression in vitro. Local IRF7 silencing in a collagen-induced arthritis mouse model attenuates joint inflammation, synovial hyperplasia, and bone erosion while increasing regulatory T cells. Local targeting of IRF7 offers a precise therapeutic strategy to mitigate RA synovial inflammation without systemic immunosuppression.

Osteoporosis is characterized by decreased bone mass and accumulation of adipocytes in the bone marrow. The mechanism underlying the imbalance between osteoblastogenesis and adipogenesis in bone marrow mesenchymal stem cells (BMSCs) remains unclear. We found that ALG5 was significantly downregulated in BMSCs from osteoporotic specimens. ALG5 knockdown inhibited osteogenic differentiation and increased adipogenic differentiation of BMSCs. ALG5 deficiency diminished the N-glycosylation of SLC6A9, thereby altering its protein stability and disrupting SLC6A9-mediated glycine uptake in BMSCs. ALG5 overexpression by adeno-associated virus serotype 9 (rAAV9) alleviated bone loss in OVX mice. Taken together, our findings suggest a novel role for the ALG5-SLC6A9-glycine axis in the imbalance of BMSC differentiation in osteoporosis. Moreover, we identify ALG5 overexpression as a potential therapeutic strategy for treating osteoporosis.

The entheses are the sites where tendons or ligaments insert into osseous structures and play a crucial role in transmitting mechanical stress from muscles to bones. Under excessive mechanical loads, the entheses may sustain inflammation, leading to isolated enthesitis. However, the specific mechanisms through which enthesitis occurs have not yet been fully elucidated. In our study, we discovered that mechanical stress is a critical factor that drives fibroblasts to recruit neutrophils through the secretion of leukemia inhibitory factor (LIF). Further research revealed that fibroblasts convert mechanical stress, a physical signal, into a chemical signal through the Piezo mechanosensitive ion channel, subsequently activating the transcription factor NFAT1 and upregulating LIF expression. This study not only helps elucidate the mechanisms underlying the development of enthesitis but also offers potential insights into the clinical management and treatment of patients with enthesitis.

Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.

The dysregulation of bone marrow mesenchymal stem cells (BM-MSCs) is crucial in the pathogenesis of osteoporosis, and adipogenic differentiation of BM-MSCs is considered an essential factor in this process. However, the mechanisms underlying the regulation of MSC adipogenic differentiation require further investigation. MGP (Matrix Gla Protein) was reported to impair the osteogenic differentiation. However, the mechanisms through which MGP regulates osteoporosis and bone-fat imbalance in MSCs are still unclear. In this study, we confirmed that the expression of MGP upregulated in osteoporosis and has a negative correlation with BMD (bone mineral density). Gain- and loss-of-function experiments were performed to ensure the role of MGP in MSC adipogenic differentiation. Mechanistically, MGP increased intracellular free Ca2+ levels and enhanced CaMKII phosphorylation, which in turn activated RIP140 protein degradation. This led to an increase in the transcription of FABP3, ultimately promoting adipogenic differentiation in MSCs. Furthermore, we demonstrated that using recombinant adeno-associated virus 9 (rAAV9) to silence MGP has the effect of alleviating bone loss and reversing the excessive bone marrow adipose tissue in mice with osteoporosis. In summary, our research has unveiled the regulatory role of MGP/Ca2+/CaMKII/RIP140/FABP3 axis in adipogenic differentiation in MSC and it might be a promising approach for osteoporosis treatment.

Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis. Moreover, although previous studies have reported that the proviral integration of Moloney virus 2 (Pim2) kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells, its role in inflammatory arthritis remains unclear. In this study, we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization. Specifically, Pim2 directly phosphorylates PGK1-S203, PDHA1-S300, and PFKFB2-S466, thereby promoting glycolytic reprogramming. Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collagen-induced arthritis (CIA) model mice. Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization. Through molecular docking and dynamic simulation, bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization, thereby mitigating the progression of inflammatory arthritis. For targeted treatment, neutrophil membrane-coated bexarotene (Bex)-loaded PLGA-based nanoparticles (NM@NP-Bex) were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages, and these nanoparticles (NPs) exhibited superior therapeutic effects with fewer side effects. Taken together, the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance. NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.

Mesenchymal stem cells (MSCs) are extensively utilised to treat inflammatory diseases because of their strong immunosuppressive functions. However, these functions are strongly affected by the inflammatory microenvironment in vivo, which limits the therapeutic effect of MSCs. The present study demonstrated that TNF-α impairs the immunosuppressive effect of MSCs on T-cell proliferation. Mechanistically, TNF-α treatment decreased the expression of the H3 deacetylase HDAC5 and then led to increased super-enhancer (SE) signals and increased expression of leukaemia inhibitory factor (LIF), which results in the dysfunction of MSCs' immunosuppressive effect. Intravenous infusion of MSCs overexpressing HDAC5 increased therapeutic efficacy in SKG mice with inflammatory arthritis. Notably, TNF-α downregulated HDAC5 by promoting WTAP-mediated m6A modification of HDAC5 mRNAs, which are subsequently regulated by YTHDF2 to reduce mRNA stability. Our results reveal a synergistic epigenetic regulatory mechanism between SEs and m6A modification of MSC immunosuppressive functions and provide a novel strategy to promote the clinical therapeutic potential of MSC infusion in inflammatory diseases.

Titanium (Ti) and its alloys have been widely employed in the treatment of orthopedics and other hard tissue diseases. However, Ti-based implants are bioinert and suffer from bacterial infections and poor osseointegration in clinical applications. Herein, we successfully modified Ti with a porous N-halaminated spermidine-containing polymeric coating (Ti-SPD-Cl) through alkali-heat treatment, surface grafting and chlorination, and it has both excellent antibacterial and osteogenic abilities to significantly enhance osseointegration. The as-obtained Ti-SPD-Cl contains abundant N-Cl groups and demonstrates effective antibacterial ability against S. aureus and E. coli. Meanwhile, due to the presence of the spermidine component and construction of a porous hydrophilic surface, Ti-SPD-Cl is also beneficial for maintaining cell membrane homeostasis and promoting cell adhesion, exhibiting good biocompatibility and osteogenic ability. The rat osteomyelitis model demonstrates that Ti-SPD-Cl can effectively suppress bacterial infection and enhance bone-implant integration. Thus, Ti-SPD-Cl shows promising clinical applicability in the prevention of orthopedic implant infections and poor osseointegration.

Iron deficiency is a prevalent nutritional deficit associated with organ damage and dysfunction. Recent research increasingly associates iron deficiency with bone metabolism dysfunction, although the precise underlying mechanisms remain unclear. Some studies have proposed that iron-dependent methylation-erasing enzyme activity regulates cell proliferation and differentiation under physiological or pathological conditions. However, it remains uncertain whether iron deficiency inhibits the activation of quiescent mesenchymal stem cells (MSCs) by affecting histone demethylase activity. In our study, we identified KDM4D as a key player in the activation of quiescent MSCs. Under conditions of iron deficiency, the H3K9me3 demethylase activity of KDM4D significantly decreased. This alteration resulted in increased heterochromatin with H3K9me3 near the PIK3R3 promoter, suppressing PIK3R3 expression and subsequently inhibiting the activation of quiescent MSCs via the PI3K-Akt-Foxo1 pathway. Iron-deficient mice displayed significantly impaired bone marrow MSCs activation and decreased bone mass compared to normal mice. Modulating the PI3K-Akt-Foxo1 pathway could reverse iron deficiency-induced bone loss.

Stem cells remain quiescent in vivo and become activated in response to external stimuli. However, the mechanism regulating the quiescence-activation balance of bone-marrow-derived mesenchymal stem cells (BM-MSCs) is still unclear. Herein, we demonstrated that CYP7B1 was the common critical molecule that promoted activation and impeded quiescence of BM-MSCs under inflammatory stimulation. Mechanistically, CYP7B1 degrades 25-hydroxycholesterol (25-HC) into 7α,25-dihydroxycholesterol (7α,25-OHC), which alleviates the quiescence maintenance effect of 25-HC through Notch3 signaling pathway activation. CYP7B1 expression in BM-MSCs was regulated by NF-κB p65 under inflammatory conditions. BM-MSCs from CYP7B1 conditional knockout (CKO) mice had impaired activation abilities, relating to the delayed healing of bone defects. Intravenous infusion of BM-MSCs overexpressing CYP7B1 could improve the pathological scores of mice with collagen-induced arthritis. These results clarified the quiescence-activation regulatory mechanism of BM-MSCs through the NF-κB p65-CYP7B1-Notch3 axis and provided insight into enhancing BM-MSCs biological function as well as the subsequent therapeutic effect.

INTRODUCTION:Osteoclasts, which are responsible for bone resorption, are specialized multinucleated cells generated from monocyte/macrophage progenitor cells or hematopoietic stem cells (HSCs). Physiological bone remodeling can become pathological, such as osteoporosis, when osteoclastogenesis is out of balance. Thousands of long noncoding RNAs (lncRNAs) influence important molecular and biological processes. Recent research has revealed gene expression regulation function that numerous lncRNAs regulate nuclear domain organization, genome stability. Furthermore, the research of lncRNAs has substantial clinical implications for the treatment of existing and new diseases. AREAS COVERED:In this review, we gather the most recent research on lncRNAs and their potential for basic research and clinical applications in osteoclast and osteoporosis. We also discuss the findings here in order to fully understand the role of lncRNAs in osteoclast differentiation and osteoporosis, as well as to provide a solid basis for future research exploring associated mechanisms and treatments. EXPERT OPINION:LncRNA has been considered as an important role in the regulation of osteoclast differentiation and osteoporosis. It is exciting to investigate pathophysiological processes in osteoporosis and the therapeutic potential of lncRNAs. We hope that this review will offer promising prospects for the development of precision and individualized approaches to treatment.

BackgroundEnvironment and genes both contribute to schizophrenia. However, the impact of different natural environments surrounding residential addresses on schizophrenia in urban settings remains unknown. This study aimed to investigate the association of urbanisation, measured by residential environments, with late-onset schizophrenia and explore whether genetic risk for schizophrenia modified the associations.MethodsWe examined the associations between residential environments and late-onset schizophrenia and its interaction with genetic risk factors in UK Biobank, followed from 2006 to 2010 (baseline) to Dec 2021. Residential environments, including greenspace, domestic garden, blue space, and total natural environment, were evaluated using land use coverage percentage. The polygenic risk score (PRS) of schizophrenia was derived using a Bayesian approach and adjusted it against ancestry. Cox proportional hazard regression model was used to assess the associations between per interquartile (IQR) increase of each type of residential environments and late-onset schizophrenia. Interactive effects of PRS and residential environments on late-onset schizophrenia were assessed on both additive and multiplicative scales.ResultsA total of 393,680 participants were included in the analysis, with 844 cases of late-onset schizophrenia being observed after 12.8 years of follow-up. Within 300 m buffer surrounding the residential addresses, per interquartile increase in greenspace (31.5 %) and total natural environment (34.4 %) were both associated with an 11 % (HR = 0.89, 95 % CI 0.80, 0.99) lower risk of late-onset schizophrenia. Domestic garden and blue space did not show significant protective effects on late-onset schizophrenia. A strong dose-response relationship between schizophrenia PRS and schizophrenia was found, while no additive or multiplicative interaction effects were present between residential environments and PRS on late-onset schizophrenia.ConclusionResidential greenspace and total natural environment may protect against late-onset schizophrenia in older people regardless of genetic risk. These findings shed light on the prevention of schizophrenia and urban planning to optimise ecosystem benefits linked to schizophrenia.

ObjectiveThis study aimed to investigate the effect of residential exposure to green space on the incident osteoporosis and further explore the modification effect of genetic susceptibility.MethodsParticipants from the UK Biobank were followed from 2006 to 2010 (baseline) to December 31st, 2022. Using land use coverage, we evaluated exposure to residential surrounding green space, natural environment, and domestic gardens. We used the Cox regression to examine the association between the residential environment and incident osteoporosis. The interactive effects between polygenic risk score (PRS) of osteoporosis and residential environments on incident osteoporosis were investigated.ResultsThis study included 292,662 participants. Over a median follow-up period of 13.65 years, we documented 9177 incidents of osteoporosis. Per interquartile (IQR) increase in greenness and natural environment at a 300 m buffer was associated with a 4% lower risk of incident osteoporosis [HR = 0.96, 95% CI: (0.93, 0.99)] and [HR = 0.96, 95% CI (0.93, 0.98)], respectively. We did not identify any interactive effects between genetic risk and residential environment on incident osteoporosis.ConclusionsThis study found that public greenness and natural environments could reduce the risk of incident osteoporosis regardless of genetic predisposition. Developing sustainable and publicly accessible natural environments might benefit populations' bone health.

Objectives: The global prevalence of osteoporosis is rising, yet it is unclear whether people with osteoporosis have a higher risk of depression than those without osteoporosis. Study design: A cross-sectional study.Methods: We used nationally representative data from the US National Health and Nutrition Examination Survey (NHANES) in 2005-2006, 2007-2008, 2009-2010, 2013-2014, and 2017-2020. The diagnosis of osteoporosis was based on the bone mineral density of the femoral neck measured by dual-energy X-ray absorptiometry. Depression was assessed by the Patient Health Questionnaire-9 (PHQ-9), with a score >= 5 as depressive symptoms and a score >= 10 as probable depression. We used logistic regression models to evaluate the association between osteoporosis and depressive symptoms and probable depression.Results: We included 11,603 adults (aged 50 years and older, 52.3% male) and observed 5.2% of them had osteoporosis. 31.9% of these osteoporotic people had depressive symptoms, and 10.0% had probable depression. Compared to participants without osteoporosis, those with osteoporosis were 1.73 times more likely to experience depressive symptoms (odds ratio [OR] = 1.73, 95% confidence interval [CI] 1.20-2.50) and 1.91 times more likely to experience probable depression (OR = 1.91, 95% CI 1.02-3.59), after adjusting for sex, age, race/ethnicity, education, marital status, family income, body mass index, smoking, physical activity, and alcohol abuse. Moderate-to-vigorous activities mediated the associations between osteoporosis and depression and depressive symptoms.Conclusions: Osteoporosis is an independent risk factor for depression. This study highlights the need to evaluate the mental well-being of patients with osteoporosis in clinical and primary health care.(c) 2023 The Authors. Published by Elsevier Ltd on behalf of The Royal Society for Public Health. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).