Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

CircIRAK3 exerts negative feedback regulation on inflammation by binding to HNRNP U and destabilizing proinflammatory cytokine mRNA in osteoarthritis and chondrogenesis.

Osteoarthritis (OA) is the most prevalent age-related and degenerative joint disease with limited treatment options. Previous studies have identified the therapeutic effects of mesenchymal stem cells (MSCs) therapy. Nevertheless, chronic inflammation impedes MSCs therapeutic effect. There have been reports suggesting that circular RNAs (circRNAs) are involved in OA and chondrogenesis. The combination of MSCs and circRNAs in therapies appears to be a promising option. In this study, we identified circIRAK3 as a significant regulator in cartilage degeneration and chondrogenesis through high-throughput sequencing analyses. We observed increased circIRAK3 in OA cartilage and during MSCs chondrogenesis. Knockdown of circIRAK3 resulted in excessive apoptosis, inhibited proliferation, and degradation of chondrocytes, along with the inhibition of MSCs chondrogenesis. Mechanistically, circIRAK3 bound to HNRNP U and competitively prevented its binding to IL-1ß, TNFα, and IL6 mRNA, thereby promoting mRNA degradation. Notably, circIRAK3 expression in plasma increased with higher OARSI scores. Intra-articular injection of adeno-associated virus-circIRAK3 delayed cartilage degeneration and reduced inflammation in DMM mouse model. Our study highlights a compensatory regulation network of circIRAK3 in chondrocytes in response to inflammation. CircIRAK3 has the potential to serve as a new therapeutic target for OA. Furthermore, therapies targeting circIRAK3 combined with MSCs hold promise.

Progranulinopathy: A diverse realm of disorders linked to progranulin imbalances.

Progranulin (PGRN), encoded by the GRN gene in humans, was originally isolated as a secreted growth factor that implicates in a multitude of processes ranging from regulation of tumorigenesis, inflammation to neural proliferation. Compelling evidence indicating that GRN mutation can lead to various common neuronal degenerative diseases and rare lysosomal storage diseases. These findings have unveiled a critical role for PGRN as a lysosomal protein in maintaining lysosomal function. The phenotypic spectrum of PGRN imbalance has expanded to encompass a broad spectrum of diseases, including autoimmune diseases, metabolic, musculoskeletal and cardiovascular diseases. These diseases collectively referred to as Progranulinopathy- a term encompasses the wide spectrum of disorders influenced by PGRN imbalance. Unlike its known extracellular function as a growth factor-like molecule associated with multiple membrane receptors, PGRN also serves as an intracellular co-chaperone engaged in the folding and traffic of its associated proteins, particularly the lysosomal hydrolases. This chaperone activity is required for PGRN to exert its diverse functions across a broad range of diseases, encompassing both the central nervous system and peripheral systems. In this comprehensive review, we present an update of the emerging role of PGRN in Progranulinopathy, with special focus on elucidating the intricate interplay between PGRN and a diverse array of proteins at various levels, ranging from extracellular fluids and intracellular components, as well as various pathophysiological processes involved. This review seeks to offer a comprehensive grasp of PGRN's diverse functions, aiming to unveil intricate mechanisms behind Progranulinopathy and open doors for future research endeavors.

FUNDC1/PFKP-mediated mitophagy induced by KD025 ameliorates cartilage degeneration in osteoarthritis.

Osteoarthritis (OA) is the most common joint disease, but no disease-modifying drugs have been approved for OA treatment. Mitophagy participates in mitochondrial homeostasis regulation by selectively clearing dysfunctional mitochondria, which might contribute to cartilage degeneration in OA. Here, we provide evidence of impaired mitophagy in OA chondrocytes, which exacerbates chondrocyte degeneration. Among the several classic mitophagy-regulating pathways and receptors, we found that FUNDC1 plays a key role in preserving chondrocyte homeostasis by inducing mitophagy. FUNDC1 knockdown in vitro and knockout in vivo decreased mitophagy and exacerbated mitochondrial dysfunction, exacerbating chondrocyte degeneration and OA progression. FUNDC1 overexpression via intra-articular injection of adeno-associated virus alleviated cartilage degeneration in OA. Mechanistically, our study demonstrated that PFKP interacts with and dephosphorylates FUNDC1 to induce mitophagy in chondrocytes. Further analysis identified KD025 as a candidate drug for restoring chondrocyte mitophagy by increasing the FUNDC1-PFKP interaction and thus alleviating cartilage degeneration in mice with DMM-induced OA. Our study highlights the role of the FUNDC1-PFKP interaction in chondrocyte homeostasis via mitophagy induction and identifies KD025 as a promising agent for treating OA by increasing chondrocyte mitophagy.

Mendelian randomization to evaluate the causal relationship between liver enzymes and the risk of six specific bone and joint-related diseases.

Background: Studies of liver dysfunction in relation to bone and joint-related diseases are scarce, and its causality remains unclear. Our objective was to investigate whether serum liver enzymes are causally associated with bone and joint-related diseases using Mendelian randomization (MR) designs. Methods: Genetic data on serum liver enzymes (alkaline phosphatase (ALP); alanine transaminase (ALT); gamma-glutamyl transferase (GGT)) and six common bone and joint-related diseases (rheumatoid arthritis (RA), osteoporosis, osteoarthritis (OA), ankylosing spondylitis, psoriatic arthritis, and gout) were derived from independent genome-wide association studies of European ancestry. The inverse variance-weighted (IVW) method was applied for the main causal estimate. Complementary sensitivity analyses and reverse causal analyses were utilized to confirm the robustness of the results. Results: Using the IVW method, the positive causality between ALP and the risk of osteoporosis diagnosed by bone mineral density (BMD) at different sites was indicated (femoral neck, lumbar spine, and total body BMD, odds ratio (OR) [95% CI], 0.40 [0.23-0.69], 0.35 [0.19-0.67], and 0.33 [0.22-0.51], respectively). ALP was also linked to a higher risk of RA (OR [95% CI], 6.26 [1.69-23.51]). Evidence of potential harmful effects of higher levels of ALT on the risk of hip and knee OA was acquired (OR [95% CI], 2.48 [1.39-4.41] and 3.07 [1.49-6.30], respectively). No causal relationship was observed between GGT and these bone and joint-related diseases. The study also found that BMD were all negatively linked to ALP levels (OR [95% CI] for TBMD, FN-BMD, and LS-BMD: 0.993 [0.991-0.995], 0.993 [0.988-0.998], and 0.993 [0.989, 0.998], respectively) in the reverse causal analysis. The results were replicated via sensitivity analysis in the validation process. Conclusions: Our study revealed a significant association between liver function and bone and joint-related diseases.

Causal relationship between type 2 diabetes mellitus and bone mineral density: a Mendelian randomization study in an East Asian population.

It remains unclear whether the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) reflects causality in East Asian populations. Herein, a Mendelian randomization study conducted in East Asian population enhances the current clinical cognition that T2DM is not associated with reduction in BMD. PURPOSE: A Mendelian randomization (MR) approach was utilized to investigate the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) in East Asian populations. METHODS: Genome-wide association study summary data from BioBank Japan were used to identify genetic variants strongly related to T2DM risk (36,614 cases and 155,150 controls) and osteoporosis (7788 cases and 204,665 controls). Heel BMD GWAS data of 1260 East Asian people from ieu open gwas project was considered as a second outcome. Inverse variance-weighted (IVW) analysis was mainly applied; MR-Egger and the weighted median were also used to obtain robust estimates. A series of sensitivity analyses including Cochran's Q test, MR-Egger regression, and leave-one-out analysis were used to detect pleiotropy or heterogeneity. RESULTS: In the main analysis, IVW estimates indicated that T2DM significantly associated with the risk of osteoporosis (odds ratio = 0.92, 95% CI: 0.86-0.99, p = 0.016) and with higher BMD (OR: 1.25, 95% CI: 1.06-1.46, p = 6.49 × 10-3). Results of comprehensive sensitivity analysis were consistent with the main causality estimate. Horizontal pleiotropy and heterogeneity were absent in our MR study. CONCLUSIONS: T2DM is not associated with reduction in BMD in terms of genetic polymorphism in East Asian populations.

A Mendelian randomization study on causal effects of leisure sedentary behaviour on the risk of rheumatoid arthritis.

BACKGROUND: The causal inference between leisure sedentary behaviour (LSB) and rheumatoid arthritis (RA) is still controversial because of potential residual confounding and reverse causality. METHODS: The present study used publicly available large-scale genome-wide association studies (GWAS) of LSB (television watching, computer use, and driving) and RA to perform a two-sample Mendelian randomization (MR) study to evaluate the causal effect of LSB on the risk of RA. We detected significant causal associations using the multiplicative random effects-inverse variance weighted (MRE-IVW) method, the maximum likelihood, robust adjusted profile scores, the weighted median, MR-Egger regression, and several complementary sensitivity analyses. Risk factor analysis was also conducted to further investigate potential mediators linking causal inference. RESULTS: Increased genetic liability to leisure television watching was significantly associated with a higher risk of RA (MRE-IVW method; OR = 2.46, 95% CI 1.77-3.41; p = 8.35 × 10-8 ). MR estimates indicated that prolonged leisure computer use was causally associated with a lower risk of RA (MRE-IVW method; OR = 0.23, 95% CI 0.12-0.46; p = 2.19 × 10-5 ). However, we found no evidence for a causal effect of leisure driving on the risk of RA (MRE-IVW method; OR = 0.59, 95% CI 0.10-3.41; p = 0.557). No pleiotropy was detected by the sensitivity analysis. CONCLUSIONS: This study supports a causal association between prolonged leisure television watching and an increased risk of RA. Additionally, prolonged computer use might be a protective factor for RA.

Mendelian randomization study on the causal effects of systemic lupus erythematosus on major depressive disorder.

The vast majority of epidemiological studies suggested a link between systemic lupus erythematosus (SLE) and major depressive disorder (MDD). However, the causality for SLE on the risk of MDD remained unknown due to confounding factors or reverse causality. Herein, we investigated the causality between SLE and MDD in those of European ancestry by a Mendelian randomization (MR) approach. Summary genetic data of cases with SLE/MDD were derived from independent largest public genome-wide association study. Forty-six single nucleotide polymorphisms associated with SLE were used as instrumental variables. The main causal inference was carried out using the MRE-IVW method. Additional, reverse-direction MR and multivariable MR analyses were further performed. Result indicated that SLE was causally associated with a lower risk of MDD (using the MRE-IVW method, odds ratio [OR] = 0.983, 95% confidence interval [CI] = 0.974-0.991, p = 1.18 × 10-4). Complementary analysis found no heterogeneity or horizontal pleiotropy. Multivariate MR analysis yielded consistent results (OR = 0.981; 95% CI = 0.969-0.993; p = 2.75 × 10-3). Reverse-direction MR analysis suggested non-causal relationship of MDD on the risk of SLE (using the IVW method, OR = 0.846, 95% CI = 0.345-2.072; p = 0.714). Thus, this is the first study providing evidence of potential causal links between SLE and MDD and further related research is needed.

Causal relationship between 14 site-specific cancers and venous thromboembolism.

Background: It has been observed that cancer and venous thromboembolism (VTE) are associated, but anticancer therapy may violate the causality. Therefore, this study aimed to elucidate the causal relationship of various cancers to VTE using Mendelian randomization (MR). Methods: Three MR methods were used to estimate causal effects: Inverse variance weighted (IVW), MR-Egger and weighted median. Sensitivity analyses included Cochran's Q-test, MR-Egger intercept test and MR-PRESSO. Gene ontology enrichment analysis was performed to elucidate the underlying mechanisms of VTE development in cancer patients. Results: The primary IVW approach showed that non-Hodgkin's lymphoma (NHL) might increase the risk of VTE (odds ratio [OR]: 1.20, 95% confidence interval [95% CI]: 1.00-1.44, p = 0.045), while melanoma possibly reduced the risk of VTE (OR: 0.89, 95% CI: 0.82-0.97, p = 0.006), although there was no significance after adjustment for multiple testing. No association was observed between VTE risk and other site-specific cancers. Gene ontology enrichment analysis revealed that vitamin D played an important role in the development of VTE in cancer patients. Conclusions: Our findings suggested that genetically predicted NHL was associated with higher VTE risk, whereas melanoma had lower VTE risk compared with other site-specific cancers. Moreover, this study suggested that anticancer therapy and increased extensive examination might play a more important role in VTE development than the nature of cancer.

Causal relationship between educational attainment and the risk of rheumatoid arthritis: a Mendelian randomization study.

BACKGROUND: Educational attainment is moderately heritable and inversely associated with the risk of rheumatoid arthritis. However, the causality from educational attainment on rheumatoid arthritis remained unknown. Here, we aimed to determine whether educational attainment is causally associated with rheumatoid arthritis (RA) by using Mendelian randomization (MR) approach. METHODS: Summary statistics data for RA were obtained from an available, published meta-analysis of genome-wide association studies (GWAS) that included 14,361 RA cases and 43,923 controls of European ancestry. The instrumental variables for educational attainment were obtained from a GWAS meta-analysis that included over 1 million individuals (N = 1,131,881) of European ancestry. MR analyses were mainly performed using the inverse-variance weighted (IVW) method. Sensitivity analyses were further performed to test the robustness of the association using the weighted median method, MR-Egger, Cochran Q test, "leave-one-out" analysis and MR-PRESSO test. RESULTS: A total of 387 SNPs were employed as instrumental variables in our MR analysis. Genetically predicted higher educational attainment was associated with a significantly lower risk of RA using the IVW method (odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.34-0.52; p = 1.78 × 10- 14). The weighted median method and MR Egger regression analysis yielded consistent results. The effect estimate remained robust after the outlier variants and SNPs (associated with the confounding factors) were excluded. "Leave-one-out" analysis confirmed the stability of our results. Additionally, the results suggested the absence of the horizontal pleiotropy. CONCLUSIONS: The MR analysis supported a potential inverse causative relationship between educational attainment and the risk of RA.

Causal Relationship Between Parathyroid Hormone and the Risk of Osteoarthritis: A Mendelian Randomization Study.

BACKGROUND: Previous studies have demonstrated an inverse association between parathyroid hormone (PTH) and the risk of osteoarthritis (OA). However, it remains unknown whether such association reflects causality. We aimed to apply a Mendelian randomization (MR) approach to investigate the causal association between PTH and OA. MATERIALS AND METHODS: We performed a two-sample MR analysis using summary statistics from 13 cohorts (PTH, N = 29,155) and a recent genome-wide association study meta-analysis (OA, N = 455,221) by the UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). MR analyses were carried out mainly using the inverse-variance-weighted method. Sensitivity analyses were performed to test the robustness of the associations using the weighted median method, the MR-Egger method, and "leave-one-out" analysis. Analyses were performed again to test whether the associations remained statistically significant after excluding any outlier variants that were detected using the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) test. RESULTS: Five single-nucleotide polymorphisms (SNPs) were selected as instrumental variables at the genome-wide significance threshold (p < 5 × 10-8). The causal effect between PTH and OA was genetically predicted using the inverse-variance-weighted method (odds ratio = 0.67, 95% confidence interval: 0.50-0.90; p = 0.008). This result was borne out using the weighted median method (odds ratio = 0.73, 95% confidence interval: 0.60-0.90; p = 0.004). The causality remained robust after discarding the outlier variants as well as SNPs associated with confounding factors. CONCLUSION: MR analysis supported a potential causative relationship between decreased serum circulating PTH and a higher risk of hip and knee OA.