Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.

Although osteoarthritis (OA) has been traditionally regarded as a non-inflammatory disease, reports increasingly suggest that it is inflammatory, at least in certain patients. OA patients often exhibit inflammatory infiltration of synovial membranes by macrophages, T cells, mast cells, B cells, plasma cells, natural killer cells, dendritic cells, granulocytes, etc. Although previous reviews have summarized the knowledge of inflammation in the pathogenesis of OA, as far as we know, no report review our current understanding about T cells, especially, each T cell subtype, in the biology of OA. This review highlights the current understanding of the role of T cells in the pathogenesis of OA, with attention to Th1 cells, Th2 cells, Th9 cells, Th17 cells, Th22 cells, regulatory T cells, follicular helper T cells, cytotoxic T cells, T memory cells, and even unconventional T cells (e.g., γδ T cells and cluster of differentiation 1 restricted T cells). The findings highlight the importance of T cells to the development and progression of OA and suggest new therapeutic approaches for OA patients based on the manipulation of T-cell responses.

Emerging evidence suggests that dysbiosis in gut microbiota may contribute to the occurrence or development of several rheumatic diseases. Since gut microbiota dysbiosis is potentially modifiable, it has been postulated to be a promising preventive or therapeutic target for rheumatic diseases. However, the current understanding on the potential associations between gut microbiota and rheumatic diseases is still inadequate. Therefore, we aimed to synthesise the accumulating evidence for the relation of gut microbiota to rheumatic diseases. The PubMed, Embase and Cochrane Library were searched from inception to March 11, 2022 to include observational studies evaluating the associations between gut microbiota and rheumatic diseases. Standardised mean difference (SMD) of α-diversity indices between rheumatic diseases and controls were estimated using random-effects model. β-diversity indices and relative abundance of gut microbes were summarised qualitatively. Of the included 92 studies (11,998 participants), 68 provided data for α-diversity. Taken together as a whole, decreases in α-diversity indices were consistently found in rheumatic diseases (observed species: SMD = −0.36, [95%CI = −0.63, −0.09]; Chao1: SMD = −0.57, [95%CI = −0.88, −0.26]; Shannon index: SMD = −0.33, [95%CI = −0.48, −0.17]; Simpson index: SMD = −0.32, [95%CI = −0.49, −0.14]). However, when specific rheumatic diseases were examined, decreases were only observed in rheumatoid arthritis (observed species: SMD = −0.51, [95%CI = −0.78, −0.24]; Shannon index: SMD = −0.31, [95%CI = −0.49, −0.13]; Simpson index: SMD = −0.31, [95%CI = −0.54, −0.08]), systemic lupus erythematosus (Chao1: SMD = −1.60, [95%CI = −2.54, −0.66]; Shannon index: SMD = −0.63, [95%CI = −1.08, −0.18]), gout (Simpson index: SMD = −0.64, [95%CI = −1.07, −0.22]) and fibromyalgia (Simpson index: SMD = −0.28, [95%CI = −0.44, −0.11]), whereas an increase was observed in systemic sclerosis (Shannon index: SMD = 1.25, [95%CI = 0.09, 2.41]). Differences with statistical significance in β-diversity were consistently reported in ankylosing spondylitis and IgG4-related diseases. Although little evidence of disease specificity of gut microbes was found, shared alterations of the depletion of anti-inflammatory butyrate-producing microbe (i.e., Faecalibacterium) and the enrichment of pro-inflammatory microbe (i.e., Streptococcus) were observed in rheumatoid arthritis, Sjögren's syndrome and systemic lupus erythematosus. Gut microbiota dysbiosis was associated with rheumatic diseases, principally with potentially non-specific, shared alterations of microbes. National Natural Science Foundation of China (81930071, 81902265, 82072502 and U21A20352).

Whether a gut-joint axis exists to regulate osteoarthritis is unknown. In two independent cohorts, we identified altered microbial bile acid metabolism with reduced glycoursodeoxycholic acid (GUDCA) in osteoarthritis. Suppressing farnesoid X receptor (FXR)—the receptor of GUDCA—alleviated osteoarthritis through intestine-secreted glucagon-like peptide 1 (GLP-1) in mice. GLP-1 receptor blockade attenuated these effects, whereas GLP-1 receptor activation mitigated osteoarthritis. Osteoarthritis patients exhibited a lower relative abundance of Clostridium bolteae , which promoted the formation of ursodeoxycholic acid (UDCA), a precursor of GUDCA. Treatment with C. bolteae and Food and Drug Administration–approved UDCA alleviated osteoarthritis through the gut FXR–joint GLP-1 axis in mice. UDCA use was associated with lower risk of osteoarthritis-related joint replacement in humans. These findings suggest that orchestrating the gut microbiota–GUDCA–intestinal FXR–GLP-1–joint pathway offers a potential strategy for osteoarthritis treatment.

Objectives Early-onset osteoarthritis (OA) is an emerging health issue amidst the escalating prevalence of overweight and obesity. However, there are scant data on its disease, economic burden and attributable burden due to high body mass index (BMI). Methods Using data from the Global Burden of Diseases Study 2019, we examined the numbers of incident cases, prevalent cases, years lived with disability (YLDs) and corresponding age-standardised rates for early-onset OA (diagnosis before age 55) from 1990 to 2019. The case definition was symptomatic and radiographically confirmed OA in any joint. The average annual percentage changes (AAPCs) of the age-standardised rates were calculated to quantify changes. We estimated the economic burden of early-onset OA and attributable burden to high BMI. Results From 1990 to 2019, the global incident cases, prevalent cases and YLDs of early-onset OA were doubled. 52.31% of incident OA cases in 2019 were under 55 years. The age-standardised rates of incidence, prevalence and YLDs increased globally and for countries in all Sociodemographic Index (SDI) quintiles (all AAPCs>0, p<0.05), with the fastest increases in low-middle SDI countries. 98.04% of countries exhibited increasing trends in all age-standardised rates. Early-onset OA accounts for US$46.17 billion in healthcare expenditure and US$60.70 billion in productivity loss cost in 2019. The attributable proportion of high BMI for early-onset OA increased globally from 9.41% (1990) to 15.29% (2019). Conclusions Early-onset OA is a developing global health problem, causing substantial economic costs in most countries. Targeted implementation of cost-effective policies and preventive intervention is required to address the growing health challenge.