To overcome negative adverse effects and improve therapeutic index of dexamethasone (Dex) in rheumatoid arthritis (RA), we developed a novel sustained release formulation-intra-articular injectable dexamethasone-loaded thermosensitive hydrogel (DLTH) with chitosan-glycerin-borax as carrier for the remission of inflammation and pain. The focus of this article is to explore both anti-inflammatory and pain-relieving effects of DLTH joint injection in bovine type-II collagen-induced arthritis (CIA) rats. Methods: Wistar rats were randomized into three groups, including the normal group (n=6), the model group (n=6) and the DLTH group (n=10). Joint injection of DLTH (1mg/kg Dex per rat) was injected on day 12 in the DLTH group twice a week for three weeks. Clinical signs of body weight, paw swelling and arthritis scores, histologic analysis, hind paw mechanical withdrawal threshold (MWT), plantar pressure pain threshold (PPT) were taken into consideration. Serum contents of IL-17A, prostaglandin E2 (PGE2), prostacyclin 2 (PGI2) and prostaglandin D2 (PGD2), real-time polymerase chain reaction (PCR) analysis of inflammatory factors and pain-related mediators in synovium and dorsal root ganglia (DRG), Western blotting of NF-κB in synovium were all evaluated. Results: Paw swelling, arthritis scores and joint inflammation destruction were all attenuated in the DLTH-treated group. Results showed that DLTH not only down-regulated serum IL-17A, but also mRNA levels of inflammatory factors and NGF, and key proteins contents of the NF-κB pathway in synovium. Increases of MWT and PPT in DLTH-treated rats elucidated pain-reducing effects of DLTH. Elevated serum PGD2 levels and declines of serum PGE2 and PGI2, and inflammatory and pain-related genes in DRGs in the DLTH group were also recorded. Conclusion: These data elucidated that DLTH joint injection impeded synovial inflammation processes through down-regulating transcription activity of NF-κB pathway, and intraarticular DLTH may aid in the regulation of RA pain through regulating inflammation and pain conduction process.

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Background: Metformin (MF) is a widely used biguanide oral hypoglycemic agent, which has obvious anti-inflammatory and immunomodulatory effects. However, the mechanism of MF on rheumatoid arthritis (RA) remains uncertain. In this study, we investigated the therapeutic effects of MF on collageninduced arthritis (CIA).Methods: CIA was induced in rats by intradermal injection of a mixture of bovine type II collagen and incomplete Freund's adjuvant (IFA) on day 0 and day 7 through the base of the tail. Intraperitoneal injection of MF (100 mg/kg) was given every 3 days, from day 14 for 3 weeks. The effects of MF on arthritisinduced systemic inflammation and synovitis were studied by pathological analysis of the knee joint and serological examination of peripheral blood in CIA rats. The bone protection effect of MF was studied by microscopic computed tomography (micro-CT) and histological analysis of the knee joint. The effects of MF on chondrocytes in CIA rats were studied by detecting the relevant pro-apoptotic mediators in the chondrocytes.Results: After administration of MF in CIA rats, systemic inflammation and synovitis caused by arthritis were significantly suppressed. Histomorphometry and micro-CT analysis of the knee joint revealed that MF can protect bone by inhibiting the changes of trabecular bone in CIA rats. Histological analysis of the knee joint found that MF can inhibit osteoclast formation and degradation of the cartilage layer matrix. Detection of the relevant pro-apoptotic mediators in chondrocytes revealed that MF can significantly inhibit the apoptosis of chondrocytes in CIA rats.Conclusions: Our study showed that MF can inhibit systemic inflammation and synovitis and plays a role in bone protection by inhibiting cartilage layer matrix degradation, osteoclast formation, and chondrocyte apoptosis.

Background: We utilized the destabilization of medial meniscus (DMM)-induced mice to illustrate the osteoarthritis (OA) suppressing and pain-relieving effects of a novel prolonged-release intra-articular (IA)dexamethasone-loaded thermo-sensitive hydrogel (DLTH).Methods: The effects of temperature and pH on DLTH formation and in vitro DLTH release profile were assessed. C57BL/6J mice were randomly divided into three groups: Ctrl group Model group and DLTH group. The DLTH group received joint injections of 10 μL DLTH (1 mg/kg) into the right knee once a week from week 2 to week 11. We performed micro-computed tomography (Micro-CT) and histological analyses of safranin O-fast green, hematoxylin and eosin, and tartrate-resistant acid phosphatase in knee joints. We also carried out immunohistochemical (IHC) staining for matrix metalloproteinase-9 (MMP-9), MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs-5 in cartilage and Ki-67 in synovia. Pain behavioral testing was carried out in all mice. The serum content of prostaglandin E2 (PGE2) and real-time polymerase chain reaction (PCR) of inflammatory cytokines and pain-related factors in dorsal root ganglia (DRGs) were evaluated. Results: It took 20 minutes to form DLTH at pH 7.0 and 37 ℃. The cumulative release profiles of dexamethasone (Dex) from DLTH at 37 ℃ revealed a rapid release in the first 24 h and a sustained slow release for 7 days. In vivo study illustrated that DLTH attenuated OA bone destruction and ameliorated synovitis and progression of OA in DMM-induced mice. The chondroprotective effects of DLTH were mediated by decreased expressions of MMP-9, MMP-13, and ADAMTS-5. The results showed that IA-DLTH exerted pain-relieving effects in OA mice. Upregulation of nociceptive response time (NRT) and downregulations of serum PGE2, inflammatory factors, and pain-related mediators in DRGs of mice in the DLTH group were recorded. Conclusions: Data presented in this study elucidated that DLTH exhibited a long and lasting Dex release and it is a potential sustainable drug delivery system (DDS) to treat OA locally. IA-DLTH injection exerted chondroprotective and pain-relieving effects in DMM-induced arthritis. The involvement of MMP-9, MMP-13, ADAMTS-5, and inflammatory and pain-related factors, may account for the suppression of OA progression and pain.