ABSTRACT:We investigated the feasibility of the intra-articular injection of resveratrol for preventing the progression of existing cartilage degeneration in a mouse model of osteoarthritis (OA). The effects of resveratrol on the expression of silent information regulator 2 type 1 (SIRT1), hypoxia-inducible factor-2a (HIF-2a) and catabolic factors in OA cartilage was explored. OA was induced in the mouse knee via destabilization of the medial meniscus (DMM). Resveratrol was injected weekly into the operated knee beginning 4 weeks after surgery. The OA phenotype was evaluated via histological and immunohistochemical analyses at 8 weeks after DMM. Western blot analysis was performed to identify whether resveratrol modulated the interleukin (IL)-1b-induced expression of HIF-2a in human chondrocytes. Histologically, resveratrol treatment preserved the structural homeostasis of the articular cartilage and the subchondral bone. Following resveratrol injection, the expression of collagen type II was retained, but the expression of inducible nitric oxide synthase and matrix metalloproteinase-13 was reduced in OA cartilage. Moreover, the administration of resveratrol significantly induced the activation of SIRT1 and the inhibition of HIF-2a expression in mouse OA cartilage and in IL-1b-treated human chondrocytes. These findings indicate that the intra-articular injection of resveratrol significantly prevents the destruction of OA cartilage by activating SIRT1 and thereby suppressing the expression of HIF-2a and catabolic factors. Keywords: osteoarthritis; resveratrol; SIRT1; HIF-2a; catabolic factorThe chronic degenerative joint disorder, osteoarthritis (OA) remains the leading cause of long-term disability, and is characterized by abnormal articulation, joint instability, pain and loss of movement.1 Under physiological circumstances, cartilage homeostasis is maintained by an equivalent balance between anabolism and catabolism.2 However, this homeostasis is disrupted in OA, in which catabolism becomes more dominant, leading to the degradation of the cartilaginous extracellular matrix and the eventual destruction of cartilage structure.3,4 The degradation of articular cartilage involves pro-inflammatory cytokine expression, inflammation, increased matrix metalloproteinase (MMP) and aggrecanase expression, decreased extracellular matrix (ECM) synthesis, and chondrocyte apoptosis. Many factors, including biophysical and biochemical activities, have been reported to be responsible for initiating the pathogenesis of OA. Among these factors, hypoxia-inducible factor-2a (HIF-2a) was recently demonstrated to play a key role in the regulation of catabolic reactions in arthritic cartilage. 5,6 HIF-2a (also termed endothelial PAS domain protein-1, EPAS1), belong to the basic helix-loop-helix/ PAS transcription factor family.7 HIF-2a is regulated by its oxygen-dependent degradation and participates in the modulation of the hypoxic response by binding to hypoxia-responsive elements (HREs) in the promoters of target genes. 6,8 In a re...

Autophagy is an essential cellular homeostasis mechanism that was found to be compromised in aging and osteoarthritis (OA) cartilage. Previous studies showed that resveratrol can effectively regulate autophagy in other cells. The purpose of this study was to determine whether the chondroprotective effect of resveratrol was related to chondrocyte autophagy and to elucidate underlying mechanisms. OA model was induced by destabilization of the medial meniscus (DMM) in 10-week-old male mice. OA mice were treated with resveratrol with/without 3-MA for 8 weeks beginning 4 weeks after surgery. The local intra-articular injection of resveratrol delayed articular cartilage degradation in DMM-induced OA by OARSI scoring systems and Safranin O-fast green. Resveratrol treatment increased Unc-51-like kinase1, Beclin1, microtubule-associated protein light chain 3, hypoxia inducible factor-1α, phosphorylated AMPK, collagen-2A1, Aggrecan expressions, but decreased hypoxia inducible factor-2α, phosphorylated mTOR, matrix metalloproteinases13 and a disintegrin and metalloproteinase with thrombospondin motifs 5 expressions. The effects of resveratrol were obviously blunted by 3-MA except HIF and AMPK. These findings indicate that resveratrol intra-articular injection delayed articular cartilage degeneration and promoted chondrocyte autophagy in an experimental model of surgical DMM-induced OA, in part via balancing HIF-1α and HIF-2α expressions and thereby regulating AMPK/mTOR signaling pathway.

Hydrogels for biomedical applications were limited toward bone tissue engineering due to the poor mechanical performance. Tough hydrogels with strong and elastic features have received extensive attention, the application of which, however, was limited by their degradation. The present study introduced an approach to enhance mechanical properties of hydrogel while ensuring its degradation. Carboxyl dextran (Dex) was grafting modified by poly (ε‐caprolactone) (PCL), sequentially followed by being cross‐linked through polyethyleneglycol 400 (PEG400) to yield a gel with covalent cross‐linking units in DMSO. The gel was underwent solvent displacement in H2O to induce hydrophobic association of PCL to form non‐covalent cross‐linking units. The tough Dex‐g‐PCL hydrogel showed maximum strain of Dex‐g‐PCL hydrogel was 90% ± 6%, with the corresponding stress of 2.7 ± 0.2 MPa, which was significantly enhanced when comparing to dextran hydrogel (maximum strain 65% ± 5%, with the corresponding stress of 0.225 ± 0.06 MPa). Most hydrogel degraded after 12 w in vivo with only a little residues. Adipose‐derived stem cells (ASCs) proliferated well after being seeded in hydrogel to form micro‐mass at 14 days post‐seeding. In vitro and in vivo angiogenesis, as well as in vitro osteogenesis illustrated the potential of the Dex‐g‐PCL hydrogel carrying ASCs toward vascularized bone tissue engineering. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1120–1131, 2019.

Background Characterizing the impacts of postoperative opioid use on total knee arthroplasty (TKA) patients may help optimize the pain management after TKA. The aim of the study is to examine the prevalence and risk factors for opioid use with an enhanced-recovery programme after primary TKA. Methods We identified 361 patients undergoing TKA, and separated those on the basis of whether to receive opioid use after surgery. Themultivariate logistic regression model was used to identify independent risk factors for opioid use after primary TKA. Length of stay (LOS) and postoperative complications were also recorded and compared. Results The prevalence of opioid use after primary TKA was 23.0%. The significant risk factor was the longer operative time (OR [odds ratio] = 1.017, 95% CI [confidence interval] = 1.001 to 1.032, p = 0.034) and the protective factor was the utilization of tranexamic acid(OR= 0.355, 95% CI = 0.161 to 0.780, p = 0.010). In addition, the LOS was longer in opioid group (p < 0.05). Conclusion Considering the adverse health effects of opioid use, strategies need to be developed to prevent persistent opioid use after TKA. Reducing operative time and the application of tranexamic acid could lower the risk of opioid use with an enhanced-recovery programme after primary TKA.

Background The efficacy and safety of tranexamic acid (TXA) in reducing blood loss following total knee arthroplasty (TKA) in patients with osteoarthritis have been widely confirmed. However, there is still a paucity of the evidences regarding the effectiveness of TXA in patients with rheumatoid arthritis (RA). The purpose of the study is to explore the efficacy and safety of intravenous TXA on blood loss and transfusion risk following simultaneous bilateral TKA (SBTKA) in patients with RA. Methods As a multicenter retrospective study, a total of 74 patients diagnosed with RA who underwent SBTKA were assigned into TXA group (15 mg/kg intravenous TXA before skin incision, n = 50) and control group (no TXA use, n = 24). The primary outcomes were total blood loss (TBL) and intraoperative blood loss (IBL). The secondary outcomes were hemoglobin (Hb) and hematocrit (Hct) drop on postoperative day 3, transfusion rate and volume, ambulation time, length of stay, hospitalization expenses and the incidence of complications. Results The mean TBL, IBL and transfusion volume in TXA group were significantly lower than those in control group. The Hb and Hct drop on postoperative day 3 in control group were higher than those in TXA group (p<0.05). The similar trend was detected on transfusion rate, ambulation time and length of stay. The incidence of complications and hospitalization expenses did not differ significantly between the two groups (p>0.05). Conclusions TXA could effectively reduce blood loss, decrease transfusion risk, shorten ambulation time and length of stay following SBTKA in patients with RA, without increasing the risk of complications.