A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis.

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

Gut Clostridium sporogenes-derived indole propionic acid suppresses osteoclast formation by activating pregnane X receptor.

Bone homeostasis is maintained by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. A dramatic decrease in estrogen levels in postmenopausal women leads to osteoclast overactivation, impaired bone homeostasis, and subsequent bone loss. Changes in the gut microbiome affect bone mineral density. However, the role of the gut microbiome in estrogen deficiency-induced bone loss and its underlying mechanism remain unknown. In this study, we found that the abundance of Clostridium sporogenes (C. spor.) and its derived metabolite, indole propionic acid (IPA), were decreased in ovariectomized (OVX) mice. In vitro assays suggested that IPA suppressed osteoclast differentiation and function. At the molecular level, IPA suppressed receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced pregnane X receptor (PXR) ubiquitination and degradation, leading to increased binding of remaining PXR with P65. In vivo daily IPA administration or repeated C. spor. colonization protected against OVX-induced bone loss. To protect live bacteria from the harsh gastric environment and delay the emptying of orally administered C. spor. from the intestine, a C. spor.-encapsulated silk fibroin (SF) hydrogel system was developed, which achieved bone protection in OVX mice comparable to that achieved with repeated germ transplantation or daily IPA administration. Overall, we found that gut C. spor.-derived IPA was involved in estrogen deficiency-induced osteoclast overactivation by regulating the PXR/P65 complex. The C. spor.-encapsulated SF hydrogel system is a promising tool for combating postmenopausal osteoporosis without the disadvantages of repeated germ transplantation.

IL-17 promotes osteoclast-induced bone loss by regulating glutamine-dependent energy metabolism.

Osteoclasts consume an amount of adenosine triphosphate (ATP) to perform their bone resorption function in the development of osteoporosis. However, the mechanism underlying osteoclast energy metabolism has not been fully elucidated. In addition to glucose, glutamine (Glu) is another major energy carrier to produce ATP. However, the role of Glu metabolism in osteoclasts and the related molecular mechanisms has been poorly elucidated. Here we show that Glu is required for osteoclast differentiation and function, and that Glu deprivation or pharmacological inhibition of Glu transporter ASCT2 by V9302 suppresses osteoclast differentiation and their bone resorptive function. In vivo treatment with V9302 improved OVX-induced bone loss. Mechanistically, RNA-seq combined with in vitro and in vivo experiments suggested that Glu mediates the role of IL-17 in promoting osteoclast differentiation and in regulating energy metabolism. In vivo IL-17 treatment exacerbated OVX-induced bone loss, and this effect requires the participation of Glu or its downstream metabolite α-KG. Taken together, this study revealed a previously unappreciated regulation of IL-17 on energy metabolism, and this regulation is Glu-dependent. Targeting the IL-17-Glu-energy metabolism axis may be a potential therapeutic strategy for the treatment of osteoporosis and other IL-17 related diseases.

Bioenergetic dysfunction in the pathogenesis of intervertebral disc degeneration.

Intervertebral disc (IVD) degeneration is a frequent cause of low back pain and is the most common cause of disability. Treatments for symptomatic IVD degeneration, including conservative treatments such as analgesics, physical therapy, anti-inflammatories and surgeries, are aimed at alleviating neurological symptoms. However, there are no effective treatments to prevent or delay IVD degeneration. Previous studies have identified risk factors for IVD degeneration such as aging, inflammation, genetic factors, mechanical overload, nutrient deprivation and smoking, but metabolic dysfunction has not been highlighted. IVDs are the largest avascular structures in the human body and determine the hypoxic and glycolytic features of nucleus pulposus (NP) cells. Accumulating evidence has demonstrated that intracellular metabolic dysfunction is associated with IVD degeneration, but a comprehensive review is lacking. Here, by reviewing the physiological features of IVDs, pathological processes and metabolic changes associated with IVD degeneration and the functions of metabolic genes in IVDs, we highlight that glycolytic pathway and intact mitochondrial function are essential for IVD homeostasis. In degenerated NPs, glycolysis and mitochondrial function are downregulated. Boosting glycolysis such as HIF1α overexpression protects against IVD degeneration. Moreover, the correlations between metabolic diseases such as diabetes, obesity and IVD degeneration and their underlying molecular mechanisms are discussed. Hyperglycemia in diabetic diseases leads to cell senescence, the senescence-associated phenotype (SASP), apoptosis and catabolism of extracellualr matrix in IVDs. Correcting the global metabolic disorders such as insulin or GLP-1 receptor agonist administration is beneficial for diabetes associated IVD degeneration. Overall, we summarized the recent progress of investigations on metabolic contributions to IVD degeneration and provide a new perspective that correcting metabolic dysfunction may be beneficial for treating IVD degeneration.

Injectable photocrosslinking spherical hydrogel-encapsulated targeting peptide-modified engineered exosomes for osteoarthritis therapy.

Osteoarthritis (OA) is a common degenerative joint disease urgently needing effective treatments. Bone marrow mesenchymal stromal cell-derived exosomes (Exo) are considered good drug carriers whereas they have limitations such as fast clearance and low retention. This study aimed to overcome the limitations of Exo in drug delivery using multiple strategies. Novel photocrosslinking spherical gelatin methacryloyl hydrogel (GelMA)-encapsulated cartilage affinity WYRGRL (W) peptide-modified engineered Exo were developed for OA treatment and the performance of the engineered Exo (W-Exo@GelMA) loaded with a small inhibitor LRRK2-IN-1 (W-Exo-L@GelMA) was investigated in vitro and in vivo. The W-Exo-L@GelMA showed an effective targeting effect on chondrocytes and a pronounced action on suppressing catabolism and promoting anabolism in vitro. Moreover, W-Exo-L@GelMA remarkably inhibited OA-related inflammation and immune gene expression, rescuing the IL-1ß-induced transcriptomic responses. With enhanced retention in the joint, W-Exo-L@GelMA demonstrated superior anti-OA activity and cartilage repair ability in the OA murine model. The therapeutic effect was validated in the cultured human OA cartilage. In conclusion, photocrosslinking spherical hydrogel-encapsulated targeting peptide-modified engineered Exo exhibit notable potential in OA therapy. Engineering Exo by a series of strategies enhanced the targeting ability and retention and cartilage-targeting and Exo-mediated drug delivery may offer a novel strategy for OA treatment.Clinical trial registration: Not applciable.

Metformin Attenuates the Inflammatory Response via the Regulation of Synovial M1 Macrophage in Osteoarthritis.

Osteoarthritis (OA), the most common chronic inflammatory joint disease, is characterized by progressive cartilage degeneration, subchondral bone sclerosis, synovitis, and osteophyte formation. Metformin, a hypoglycemic agent used in the treatment of type 2 diabetes, has been evidenced to have anti-inflammatory properties to treat OA. It hampers the M1 polarization of synovial sublining macrophages, which promotes synovitis and exacerbates OA, thus lessening cartilage loss. In this study, metformin prevented the pro-inflammatory cytokines secreted by M1 macrophages, suppressed the inflammatory response of chondrocytes cultured with conditional medium (CM) from M1 macrophages, and mitigated the migration of M1 macrophages induced by interleukin-1ß (IL-1ß)-treated chondrocytes in vitro. In the meantime, metformin reduced the invasion of M1 macrophages in synovial regions brought about by the destabilization of medial meniscus (DMM) surgery in mice, and alleviated cartilage degeneration. Mechanistically, metformin regulated PI3K/AKT and downstream pathways in M1 macrophages. Overall, we demonstrated the therapeutic potential of metformin targeting synovial M1 macrophages in OA.

Inhibition of FAAH suppresses RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss partially through repressing the IL17 pathway.

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.

Titania-Nanotube-Coated Titanium Substrates Promote Osteogenesis and Suppress Osteoclastogenesis via Integrin ανß3.

The balance of bone turnover mediated by osteoclastogenesis and osteogenesis implants that could suppress osteoclastogenesis and promote osteogenesis is an appropriate treatment strategy for osteoporosis patients. Titanium is one of the most applied materials in implants. In this study, titania nanotubes (Ti-NTs) were produced by anodization at 10, 40, and 60 V. We found that Ti-NTs were nontoxic to bone marrow mesenchymal stem cells (BMSCs). Ti-NTs suppressed osteoclast formation and function in a diameter dependent manner in vitro. Furthermore, Ti-NTs enhanced the activity of osteogenesis, expressions of osteogenesis-related marker genes were increased and ß-Catenin pathway was active. Alkaline phosphatase (ALP) activity and matrix mineralization were also promoted in vitro. To explore the possible mechanisms, we performed a series of experiments to indicate the effects of Ti-NTs on cytoskeletal organization and integrin ανß3 expression of osteoclasts and osteoblasts. The results demonstrated that 90-nm-diameter Ti-NTs could suppress the expression of integrin ανß3 in osteoclast precursor cells. Interestingly, it revealed an opposite effect on BMSCs. Moreover, 90 nm-diameter Ti-NTs prevented ovariectomy (OVX)-induced bone loss. These findings indicated that Ti-NTs could inhibit osteoclastogenesis and enhance osteogenesis; it was mediated via regulation of integrin ανß3─90 nm-diameter Ti-NT revealed a good biological ability especially suited for osteoporosis treatment.

Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity.

cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.

Spinal Cord Injury: The Global Incidence, Prevalence, and Disability From the Global Burden of Disease Study 2019.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The authors aimed to estimate the incidence, prevalence and years lived with disability (YLDs) of spinal cord injury (SCI) by location, sex, age, injury site and socio-demographic index (SDI) based on the data of the Global Burden of Disease Study (GBD) 2019. SUMMARY OF BACKGROUND DATA: GBD 2019 estimates the burden of 369 diseases and injuries worldwide in 2019 and the temporal trends in the past 30 years. SCI is estimated as a result of injury from various causes. METHODS: A Bayesian meta-regression tool, DisMod-MR2.1, was used to produce the estimates. Estimated annual percentage change (EAPC) was calculated based on a linear regression mode of the age standardized rates and the calendar year to represent the temporal trends of the age standardized rates. Spearman rank order correlation was used to determine the correlation between SDI and the incidence and burden of SCI. RESULTS: Globally, there were 0.9 [95% uncertainty interval (UI), 0.7 to 1.2] million incident cases, 20.6 (95% UI, 18.9-23.6) million prevalent cases and 6.2 (95% UI, 4.5-8.2) million YLDs of total SCI in 2019. The ASPR increased (EAPC, 0.1; 95% confidence interval, -0.01 to 0.2), while the age standardized incidence rate (ASIR) (EAPC, -0.08; 95% UI, -0.24 to 0.09) and age standardized YLD rate (ASYR) (EAPC, -0.08; 95% confidence interval, -0.24 to 0.09) decreased. Males had higher ASIR and ASYR, and the rate of incidence, prevalence and YLD increased with age. Spinal injuries at neck level caused higher ASYR than injuries below neck level. A positive correlation existed between SDI and ASIR (ρ=0.1626, P <0.05), while a negative correlation was observed between SDI and EAPC of ASYR (ρ=-0.2421, P <0.01). CONCLUSION: Conclusively, the incidence and burden of SCI has increased over the last 30 years. Males and the elderly were affected to a greater degree than females and younger individuals. LEVEL OF EVIDENCE: Level III.

Global, Regional, and National Burden of Low Bone Mineral Density From 1990 to 2019: Results From the Global Burden of Disease Study 2019.

Objective: We aim to explore the global spatial prevalence and temporal trends of the burden of low bone mineral density (LBMD) worldwide, due to a lack of related studies. Design: Cross-sectional study. Methods: We used data from the Global Burden of Disease Study 2019 to conduct this study. LBMD in the GBD study includes both osteopenia and osteoporosis. The estimation for the prevalence, measured by the summary exposure value (SEV), and burden of LBMD was made in DisMod-MR 2.1, a Bayesian meta-regression tool. Correlation analysis was performed using the Spearman rank order correlation methods. The temporal trends were represented by the estimated annual percentage change (EAPC). Results: In 2019, there were 438 thousand deaths and 16.6 million DALYs attributable to LBMD, increasing by 111.1% and 93.8% respectively, compared to that in 1990. From 1990 to 2019, the prevalence of LBMD has decreased worldwide, but has increased in high-income North America. Some countries, such as the United States, Australia, Canada, and China had increased disability and mortality rates of LBMD with time. Countries with low socio-demographic index (SDI) had higher incidence and mortality rate than those with high SDI. The prevalence of LBMD was lower in males, but the attributable disability and mortality were higher in males in all years from 1990 to 2019. Conclusion: With population aging, countries worldwide, especially those with low-SDI, will face increasing challenges in reducing the burden attributable to LBMD and osteoporosis. The treatment of osteoporosis has been overlooked in men for a long time. Effective measures are warranted to control the prevalence and burden of LBMD.

Identification of Genes with Altered Methylation in Osteoclast Differentiation and Its Roles in Osteoporosis.

Osteoporosis is one of the most common metabolic skeletal diseases, which affects more than 200 million people worldwide, especially elderly and postmenopausal women. One of the main processes of osteoporosis is attenuated bone formation. Abundant evidence has confirmed that overactivated osteoclasts are responsible for the attenuated bone formation. This study aims at identifying novel methylation-associated biomarkers and therapeutic targets in osteoclasts by integrally analyzing methylation profiles and gene expression data. DNA methylation profile and gene expression data were obtained from the Gene Expression Omnibus (GEO) database. Subsequently, we integrated the two sets of data to screen for differentially expressed genes with differential methylation level (DM-DEGs) between osteoclasts and CD14+ monocytes from donors. Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to uncover the enriched functions and pathways of identified DM-DEGs. In addition, by combining protein-protein interaction analysis and receiver-operator characteristic analysis, we finally identified four hub DM-DEGs. Gene Set Enrichment Analysis was utilized to validate and investigate the potential biological functions of the four hub DM-DEGs. Finally, Real-time quantitative PCR (QPCR) was performed to validate the mRNA expression level of the four identified hub DM-DEGs during osteoclast differentiation. CCRL2, CCL18, C1QB, and SELL were highly correlated with osteoclastic differentiation and osteoporosis phenotype. QPCR revealed that the expression of CCRL2, CCL18, and C1QB was increased during osteoclast differentiation, whereas the expression of SELL was decreased. The present study indicated a connection between gene expression and DNA methylation during osteoclast differentiation and that four hub DM-DEGs in osteoclastogenesis and osteoporosis pathogenesis might be potential candidates for intensive research and therapeutic targets for the treatment of osteoporosis.

Mitochondrial pyruvate carrier blockade results in decreased osteoclastogenesis and bone resorption via regulating mitochondrial energy production.

It's widely accepted that increasing mitochondrial respiration plays a pivotal role during osteoclastogenesis. Mitochondrial pyruvate carrier (MPC) is the key transporter that links glycolysis to mitochondrial respiration but little is known about its role during osteoclastogenesis. Our goal was to determine the effects of its blockade on osteoclastogenesis and bone resorption in vivo and in vitro. To address this issue, we performed gene knockdown or pharmacologically inhibited MPC in primary bone marrow-derived monocytes (BMMs) or in an ovariectomized mouse model. We also studied the metabolic changes in RANKL-induced differentiating BMMs with MPC blockade and performed rescue experiments. We found that MPC blockade resulted in decreased osteoclastogenesis both in vivo and in vitro and inhibiting MPC significantly alleviated ovariectomy-induced trabecular bone loss. Further investigations showed that MPC blockade significantly reversed the metabolic profile related to RANK activation, including decreased intermediates involved in citric acid cycle and glutamine metabolism. Moreover, metabolic flux analysis verified that MPC blockade decreased pyruvate flux into TCA cycle with no significant effect on glycolysis. Besides, MPC blockade resulted in suppressed mitochondrial biogenesis in addition to oxidative phosphorylation. Rescue experiments revealed that inhibiting pyruvate dehydrogenase kinase (PDK) via sodium dichloroacetate (DCA), but not targeting glutamine metabolism, could reverse the effects of MPC blockade on osteoclastogenesis. These implied that the effects of MPC blockade were mediated by reduced pyruvate fuel into citric acid cycle in multiple aspects. Taken together, our data demonstrated the inhibitory effects of MPC blockade on osteoclastogenesis, which was mediated by decreased mitochondrial energy production.

Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.

Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine-triphosphate (ATP) to S-adenosylmethionine (SAM), a general methyl-group donor in vitro. MAT2A has been reported to participate in the NF-κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG-270 or genetic silencing by MAT2A-shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG-270 also prevented OVX-induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi-targeted metabolomics assay performed by LC-MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.

Inhibition of IRE1 suppresses the catabolic effect of IL-1ß on nucleus pulposus cell and prevents intervertebral disc degeneration in vivo.

Neck pain and low back pain are two of the major diseases, which causes patients a low quantify of life and a heavy economic burden, intervertebral disc degeneration (IDD) contributes to them, and the mechanism is not totally clear. The increased inflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)α and downstream signaling pathways are involved. Inositol requiring enzyme 1 (IRE1) is a crucial enzyme that regulates endoplasmic reticulum (ER) stress. It is reported that IRE1 plays an important role in the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. Considering this, we performed a series of experiments in vitro and in vivo to evaluate the role of IRE1 in the progress of IDD. We demonstrated that IRE1 pathway was induced by IL-1ß, inhibition of IRE1 suppressed the matrix degeneration of NP cells and ameliorated IDD grade in the punctured rat model. Further results indicated that inhibition of IRE1 suppressed H2O2 induced cell senescence, IL-1ß-induced cellular reactive oxygen species (ROS) level and the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. It also played a crucial role in the apoptosis of NP cells and the progress of macrophage polarization. Our findings demonstrated that inhibition of IRE1 could suppress the degeneration of NP cells and prevent IDD in vivo. IRE1 may be a potential target for IDD treatment.

Global incidence, prevalence, and disability of vertebral fractures: a systematic analysis of the global burden of disease study 2019.

BACKGROUND CONTEXT: In the context of the population growing and aging worldwide, the epidemiology, and burden of vertebral fracture have not been comprehensively analyzed. PURPOSE: To delineate the global number and rate of incidence, prevalence and burden of vertebral fracture in 2019, and the temporal trends from 1990 to 2019 by location, age, sex, and the socio-demographic index (SDI). STUDY DESIGN/SETTING: A cross-sectional study using data from the Global Burden of Disease Study 2019 (GBD study 2019). PATIENT SAMPLE: Patients with vertebral fracture documented in medical records or registrations and included in the GBD study 2019 from different countries worldwide. OUTCOME MEASURES: Age standardized incidence rate (ASIR), age standardized prevalence rate (ASPR), and age standardized years lived with disability (YLDs). METHODS: The GBD study 2019 was used to obtain data for this analysis. The incidence, prevalence and disability were analyzed by location, year, sex, age, and SDI. DisMod-MR 2.1, a Bayesian meta-regression tool, was used to produce the estimates for each value after adjustment for age, sex, and other variables. Estimated annual percentage change (EAPC) was calculated to represent the temporal trends from 1990 to 2019. Spearman's rank order correlation was used to determine the correlation between SDI and the incidence and burden of vertebral fracture. This work was supported by the Key Research and Development Program of Hubei Province of China (No. 2020BCB049), and no conflicts of interest-associated biases existed in this study. RESULTS: Globally, there were 8.6 million (95% uncertainty interval [UI], 6,6-11,3 million) incident cases, 5.3 million (95% UI, 4.6-6.2 million) prevalent cases, and 0.55 million (95% UI, 0.37-0.77 million) YLDs of vertebral fracture. Compared with 1990, the number of incident cases and YLDs in 2019 increased by 38% (95% UI, 23%-48%) and 75% (95% UI, 65%-85%), respectively, while the ASIR (EAPC, -0.28; 95% CI, -0.41 to -0.14), ASPR (EAPC, -0.12; 95% CI, -0.22 to -0.02) and age standardized YLD rate (ASYR) (EAPC, -0.13; 95% CI, -0.23 to -0.04) decreased during this period. High ASIR, ASPR and ASYR were commonly seen in high-SDI countries, such as high-income North America, Australia, Central and Eastern Europe. In the country level, positive correlations were observed between SDI and ASIR (rho, 0.596; p<.001) and ASYR (rho, 0.413; p<.001). Males had higher ASIR and ASYR worldwide in each year from 1990 to 2019. However, the incidence, and YLD rates in females surpassed that in males after 65 years of age. Increasing trends were observed for both incidence and YLD rates with age. Falls were the leading cause for vertebral fracture across all ages. CONCLUSIONS: The past thirty years have seen increasing numbers but decreasing rates of global incidence, prevalence, and disability of vertebral fractures, resulting from the growing population worldwide. With population aging, efforts are still in urgent need to address vertebral fracture related health outcomes.

A Competing Risk-based Prognostic Model to Predict Cancer-specific Death of Patients with Spinal and Pelvic Chondrosarcoma.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: The aim of this study was to develop and validate a competing-risk-based prognostic model and a nomogram for predicting the three- and five-year probability of cancer-specific death (CSD) in patients with spinal and pelvic chondrosarcoma. SUMMARY OF BACKGROUND DATA: The issue of competing risk has rarely been addressed and discussed in survival analysis of bone sarcoma. In addition, the Fine and Gray model, a more accurate method for survival analysis in the context of competing risk, has also been less reported in prognostic study of chondrosarcoma. METHODS: A total of 623 patients with spinal or pelvic chondrosarcoma were identified from the SEER database and were divided into a training and a validation cohort. These two cohorts were used to develop and validate a prognostic model to predict the 3- and 5-year probability of CSD, considering non-CSD as competing risk. The C-index, calibration plot, and decision curve analysis were used to assess the predictive performance and clinical utility of the model. RESULTS: Older age (subdistribution hazards ratio [SHR]: 1.02, 95% confidence interval [CI]: 1.01∼1.03; P = 0.013), high grade (SHR: 2.68, 95% CI: 1.80∼3.99; P < 0.001), regional involvement (SHR: 1.66, 95% CI: 1.06∼2.58; P = 0.026), distant metastasis (SHR: 5.18, 95% CI: 3.11∼8.62; P < 0.001) and radical resection (SHR: 0.38, 95% CI: 0.24∼0.60; P < 0.001) were significantly associated with the incidence of CSD. These factors were used to build a competing-risk-based model and a nomogram to predict CSD. The C-index, calibration plot, and decision curve analysis indicated that the nomogram performs well in predicting CSD and is suitable for clinical use. CONCLUSION: A competing-risk based prognostic model is developed to predict the probability of CSD of patients with spinal and pelvic chondrosarcoma. This nomogram performs well and is suitable for clinical use.Level of Evidence: 4.

Inhibition of ACLY Leads to Suppression of Osteoclast Differentiation and Function Via Regulation of Histone Acetylation.

ATP-citrate lyase (ACLY), generating most of the nucleocytosolic acetyl coenzyme A (acetyl-CoA) for histone acetylation, links cell metabolism to epigenetic regulation. Recent investigations demonstrated that ACLY activated by metabolic reprogramming played an essential role in both M1 and M2 macrophage activation via histone acetylation. Previous studies also revealed that histone methylation and acetylation were critical for transcriptional regulation of osteoclast-specific genes. Considering that osteoclast differentiation also undergoes metabolic reprogramming and the activity of ACLY is always Akt-dependent, we inferred that receptor activator of NF-κB (RANK) activation might enhance the activity of ACLY through downstream pathways and ACLY might play a role in osteoclast formation. In the current study, we found that ACLY was gradually activated during RANK ligand (RANKL)-induced osteoclast differentiation from bone marrow-derived macrophages (BMMs). Both ACLY knock-down and small molecular ACLY inhibitor BMS-303141 significantly decreased nucleocytosolic acetyl-CoA in BMMs and osteoclasts and suppressed osteoclast formation in vitro. BMS-303141 also suppressed osteoclast formation in vivo and prevents ovariectomy (OVX)-induced bone loss. Further investigations showed that RANKL triggered ACLY translocation into nucleus, consistent with increasing histone H3 acetylation, which was correlated to ACLY. The H3 lysine residues influenced by ACLY were in accordance with GCN5 targets. Using GCN5 knock-down and overexpression, we showed that ACLY and GCN5 functioned in the same pathway for histone H3 acetylation. Analysis of pathways downstream of RANK activation revealed that ACLY was Akt-dependent and predominately affected Akt pathway. With the help of RNA-sequencing, we discovered Rac1 as a downstream regulator of ACLY, which was involved in shACLY-mediated suppression of osteoclast differentiation, cytoskeleton organization, and signal transduction and was transcriptionally regulated by ACLY via histone H3 acetylation. To summarize, our results proved that inhibition of ATP-citrate lyase led to suppression of osteoclast differentiation and function via regulation of histone acetylation. Rac1 could be a downstream regulator of ACLY. © 2021 American Society for Bone and Mineral Research (ASBMR).

Suicide and accidental deaths among patients with primary malignant bone tumors.

BACKGROUND: It has been recognized that cancer is associated with a higher risk of suicide or accidental death. Earlier studies have evidenced that patients with malignant bone tumors usually experience psychological dysfunction and physical disability following surgery, which are shared risk factors between suicidal and accidental deaths. To our knowledge, there is no large population-based study on the risk of suicide or accidental death among patients with malignant bone tumors. QUESTIONS/PURPOSES: This study aimed to determine whether patients with primary malignant bone tumors are at a higher risk of suicide and accidental death than the general population and to identify the demographic and tumour-related characteristics and type of surgery associated with a higher risk of suicide and accidental death among these patients. METHODS: Overall, 50,817 patients diagnosed with primary malignant bone tumors between 1973 and 1975 were identified from the Surveillance, Epidemiology, and End Results database. The standardised mortality ratio (SMR) was calculated based on the general population's mortality data, gathered by the National Center for Health Statistics. The Cox regression model was developed to determine risk factors associated with a higher risk of suicide and accidental death. RESULTS: Patients with primary malignant bone tumors had a higher risk of suicide and accidental death than the general population in the United States (US) (SMR = 2.17; 95% confidence interval (CI) [1.80-2.62] and SMR = 1.73; 95% CI [1.54-1.95]). Compared with limb salvage, amputation significantly increased the risk of suicide (SMR = 3.99; 95% CI [2.52-6.34], hazard ratio (HR) = 2.32; 95% CI [1.31-4.09]; P < 0.01) but did not increase the risk of accidental death (SMR = 1.61; 95% CI [1.07-2.42], HR = 1.11; 95% CI [0.71-1.74]; P = 0.65). Higher suicide risk was observed among older patients whose age at diagnosis was more than 60 years (HR = 4.04; 95% CI [1.98-8.26]; P < 0.001), males (HR = 3.48; 95% CI [2.16-5.62]; P < 0.001), and whites (HR = 3.71; 95% CI [1.17-11.73]; P < 0.001). The risk of suicide and accidental death was highest in the first year after diagnosis (SMR = 2.95; 95% CI [1.86-4.69] and SMR = 2.02; 95% CI [1.48-2.74]). CONCLUSION: We first reported that patients with primary malignant bone tumors had a higher risk of suicide and accidental death than the general US population. Therefore, clinicians should pay more attention to the psychological status, physical function, and cognitive level of these survivors.