Rheumatoid arthritis (RA) is a common chronic autoimmune condition accompanied by lubrication dysfunction, inflammatory infiltration, and cartilage wear. Long-term improvements in joint lubrication, inflammation elimination, and worn cartilage repair are crucial for effective RA treatment. Herein, we present an injectable bioadhesive and lubricating hydrogel containing a dopamine-modified hyaluronic acid (DA-HA) network, sulfonated hyaluronic acid (SO₃⁻-HA) network, and kartogenin (KGN)-grafted dopamine-hybridized graphene quantum dot-supported Cu single-atom nanozyme (DAGQD@Cu@KGN SAN) designed to restore cartilage lubrication and repair worn cartilage in RA. DA within the hydrogel networks provides bioadhesion, allowing it to persist in the joint cavity for extended periods. The hydrogel with SO₃⁻ group offer lubricity, reducing friction coefficient and alleviating cartilage wear. The DAGQD@Cu@KGN SAN exhibits excellent superoxide dismutase, catalase, and •OH scavenging activities, effectively inhibiting inflammation. KGN is sustainably released from the hydrogel, recruiting bone marrow mesenchymal stem cells to repair damaged cartilage by promoting their differentiation into chondrocytes. In vivo experimental results demonstrate that this injectable bioadhesive and lubricating hydrogel not only prevents cartilage wear and tear, providing long-term anti-oxidation and anti-inflammatory effects in early RA, but also repaired damaged cartilage in late-stage RA. This bio-adhesive and lubricating hydrogel presents a potential full-cycle strategy for RA therapy.

Background: Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis. Methods: A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by Micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, Enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis. Results: C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits ( P < 0.001), higher level of bone volume to tissue volume (BV/TV, P < 0.001), bone mineral density (BMD, P < 0.001), and a lower total porosity ( P < 0.001). C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleation-induced oligomerization, suppressing the cleavage of caspase-1 ( P < 0.05) and IL-1β ( P < 0.05) stimulated by CoCrMo alloy particles. C3 and C4 also inhibited the generation of Gasdermin D-N-terminal fragment (GSDMD-NT) to regulate pyroptosis. Besides, C3 and C4 have a negative impact on osteoclast differentiation ( P < 0.05) and its function ( P < 0.05), affecting the podosome arrangement and morphologically normal podosome belts formation. Conclusion: Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.

Background: Inflammatory osteolysis after total joint replacement (TJR) may cause implant failure, periprosthetic fractures, and be a severe threat to global public health. Our previous studies demonstrated that melatonin had a therapeutic effect on wear-particles induced osteolysis. Gut microbiota is closely related to bone homeostasis, and has been proven to be affected by melatonin. However, whether melatonin could play its anti-osteolysis effects through reprogramming gut microbiota remains elusive. Results: Here, we demonstrated that melatonin could alleviate Ti-particles induced osteolysis, while this therapeutic effect was blocked by antibiotic cocktail treatment. Interestingly, transplantation of fecal microbiota from mice treated with melatonin reappeared the same beneficial effect. Analysis of the 16S rRNA revealed that melatonin could reverse dysbacteriosis triggered by osteolysis, and elevate the relative abundance of some short chain fatty acid (SCFA) producing bacteria. Moreover, butyrate was enriched by exogenous melatonin administration, while acetate and propionate did not show an evident difference. This was consistent with the results of the metagenomic approach (PICRUSt2) analysis, which revealed a general increase in the synthetic enzymes of butyrate. More importantly, direct supplementation of butyrate could also recapitulate the anti-osteolysis effect of melatonin. Further analysis identified that butyrate alleviated osteolysis via activating its receptor GPR109A, and thus to suppress the activation of NLRP3 inflammasome triggered by Ti-particles. Conclusions: Taken together, our results suggested that the benefits of melatonin mainly depend on the ability of modulating gut microbiota and regulating butyrate production. Graphic