Purpose of review Osteoarthritis is a debilitating disease leading to joint degeneration, inflammation, pain, and disability. Despite efforts to develop a disease modifying treatment, the only accepted and available clinical approaches involve palliation. Although many factors contribute to the development of osteoarthritis, the gut microbiome has recently emerged as an important pathogenic factor in osteoarthritis initiation and progression. This review examines the literature to date regarding the link between the gut microbiome and osteoarthritis. Recent findings Studies showing correlations between serum levels of bacterial metabolites and joint degeneration were the first links connecting a dysbiosis of the gut microbiome with osteoarthritis. Further investigations have demonstrated that microbial community shifts induced by antibiotics, a germ-free environment or high-fat are important underlying factors in joint homeostasis and osteoarthritis. It follows that strategies to manipulate the microbiome have demonstrated efficacy in mitigating joint degeneration in osteoarthritis. Moreover, we have observed that dietary supplementation with nutraceuticals that are joint protective may exert their influence via shifts in the gut microbiome. Summary Although role of the microbiome in osteoarthritis is an area of intense study, no clear mechanism of action has been determined. Increased understanding of how the two factors interact may provide mechanistic insight into osteoarthritis and lead to disease modifying treatments.

Osteoarthritis (OA) is a degenerative joint disease for which there are no disease modifying therapies. Thus, strategies that offer chondroprotective or regenerative capability represent a critical unmet need. Recently, oral consumption of a hydrolyzed type 1 collagen (hCol1) preparation has been reported to reduce pain in human OA and support a positive influence on chondrocyte function. To evaluate the tissue and cellular basis for these effects, we examined the impact of orally administered hCol1 in a model of posttraumatic OA (PTOA). In addition to standard chow, male C57BL/6J mice were provided a daily oral dietary supplement of hCol1 and a meniscal-ligamentous injury was induced on the right knee. At various time points post-injury, hydroxyproline (hProline) assays were performed on blood samples to confirm hCol1 delivery, and joints were harvested for tissue and molecular analyses were performed, including histomorphometry, OARSI and synovial scoring, immunohistochemistry and mRNA expression studies. Confirming ingestion of the supplements, serum hProline levels were elevated in experimental mice administered hCol1. In the hCol1 supplemented mice, chondroprotective effects were observed in injured knee joints, with dose-dependent increases in cartilage area, chondrocyte number and proteoglycan matrix at 3 and 12 weeks post-injury. Preservation of cartilage and increased chondrocyte numbers correlated with reductions in MMP13 protein levels and apoptosis, respectively. Supplemented mice also displayed reduced synovial hyperplasia that paralleled a reduction in Tnf mRNA, suggesting an anti-inflammatory effect. These findings establish that in the context of murine knee PTOA, daily oral consumption of hCol1 is chondroprotective, anti-apoptotic in articular chondrocytes, and anti-inflammatory. While the underlying mechanism driving these effects is yet to be determined, these findings provide the first tissue and cellular level information explaining the already published evidence of symptom relief supported by hCol1 in human knee OA. These results suggest that oral consumption of hCol1 is disease modifying in the context of PTOA.

Type VI collagen is well known for its role in muscular disorders, however its function in bone is still not well understood. To examine its role in bone we analyzed femoral and vertebral bone mass by micro-computed tomography analysis, which showed lower bone volume/total volume and trabecular number in Col6α2-KO mice compared with WT. Dynamic histomorphometry showed no differences in trabecular bone formation between WT and Col6α2-KO mice based on the mineral appositional rate, bone formation rate, and mineralizing perimeter. Femoral sections were assessed for the abundance of Tartrate Resistant Acid Phosphatase-positive osteoclasts, which revealed that mutant mice had more osteoclasts compared with WT mice, indicating that the primary effect of Col6a2 deficiency is on osteoclastogenesis. When bone marrow stromal cells (BMSCs) from WT and Col6α2-KO mice were treated with rmTNFα protein, the Col6α2-KO cells expressed higher levels of TNFα mRNA compared with WT cells. This was accompanied by higher levels of p-p65, a downstream target of TNFα, suggesting that BMSCs from Col6α2-KO mice are highly sensitive to TNFα signaling. Taken together, our data imply that Col6a2 deficiency causes trabecular bone loss by enhancing osteoclast differentiation through enhanced TNFα signaling. Bone is a highly dynamic tissue that depends on specialized cell types to regulate its formation and structural integrity. Bones are formed by the anabolic actions of osteoblasts. Osteoblasts share a close relationship with catabolic osteoclasts that resorb or digest bones. The coupled actions of bone resorption and subsequent bone formation is known as "bone turnover", a process that replaces and renews bone tissue that has microdamage from impact or aging. An imbalance of bone turnover results in either osteopetrosis, which is excess bone matrix, or osteopenia, which is insufficient bone matrix. In both cases, the bone is fragile and prone to breakage. Identifying novel factors that affect the osteoblast-osteoclast relationship will improve our understanding of bone turnover and pave the way for future bone therapies. Osteogenic cells are surrounded by mineralized connective tissue composed of collagen fibrils and noncollagenous proteins. These matrix components serve as nucleation sites for depositing the carbonate-rich apatite that provides strength and stiffness to the bone. Type I collagen is the most abundant collagen in bone and is composed of two α1(I) and one α2(I) chains that are assembled into a triple helical structure. These helices further aggregate to form fibrils outside the cell. The importance of type I collagen in bone is clearly illustrated

Background: Currently, opioids are the standard of care for postoperative pain management. Avoiding unnecessary opioid exposure in patients is of current interest because of widespread abuse. Methods: This is a prospective cohort study in which wide-awake, local anesthesia, no-tourniquet (WALANT) technique was used for 94 hand/upper extremity surgical patients and compared to patient cohorts undergoing similar procedures under monitored anesthesia care. Patients were not prescribed opioids postoperatively but were instead directed to use over-the-counter pain relievers. Pain scores on a visual analogue scale were collected from patients preoperatively, and on postoperative days 1 and 14. WALANT visual analogue scale scores were compared to those of the two patient cohorts who either did or did not receive postoperative opioids after undergoing similar procedures under monitored anesthesia care. Electronic medical records and New York State's prescription monitoring program, Internet System for Tracking Over-Prescribing, were used to assess prescription opioid-seeking. Information on sex, age, comorbidity burden, previous opioid exposure, and insurance coverage was also collected. Results: Decreased pain was reported by WALANT patients 14 days postoperatively compared to preoperatively and 1 day postoperatively, with a total group mean pain score of 0.37. This is lower than mean scores of monitored anesthesia care patients with and without postoperative opioids. Only two WALANT patients (2.1 percent) sought opioid prescriptions from outside providers. There was little evidence suggesting factors including sex, age, comorbidity burden, previous opioid exposure, or insurance status alter these results. Conclusion: WALANT may be a beneficial technique hand surgeons may adopt to mitigate use of postoperative opioids and reduce risk of abuse in patients.

Background: The use of minor field sterility in hand/upper extremity cases has been shown to improve workflow efficiency while maintaining patient safety. As this finding has been limited to specific procedures, we investigated the safety of performing a wide array of hand/upper extremity procedures outside the main operating room using minimal field sterility with Wide-Awake Local Anaesthesia No Tourniquet (WALANT) anaesthesia by evaluating superficial and deep infection rates across a diverse series of cases. Methods: This study was a case series conducted between October 2017 and June 2020. Of all, 217 patients underwent hand/upper extremity procedures performed in a minor procedure room via WALANT technique with field sterility. Primary outcome measures include superficial and deep surgical site infections within 14 days post-surgery. Results: Of all, 217 patients were included in this study; 265 consecutive hand/upper extremity operations were performed by a single surgeon, with notable case diversity. The majority of patients (n = 215, 99.1%) did not report or present with signs of infection before or after their operation. We report 0% 14-day and 0.37% 30-day surgical site infection rates for such hand/upper extremity procedures performed in a minor procedure room with field sterility. Conclusion: Hand/upper extremity procedures performed via WALANT technique with field sterility in a minor procedure room are associated with low surgical site infection rates. These rates are comparable to surgical site infection rates for similar surgeries performed in main operating rooms with standard sterilization procedures. Thus, the implementation of this technique may allow for improved workflow efficiency and reduced waste, all while maintaining patient safety.

The aim of this study was to analyze the anti-inflammatory effect of VA692, in comparison with celecoxib. In addition, we would establish if the new compound presents any advantages over other COX-2 inhibitors already available in therapeutic use. By iTRAQ methodology, we quantitatively analyzed the different expressed profiles in T/C-28a2 cell line treated with the studied drugs in presence of IL-1b. Methods: Human T/C-28a2 chondrocytes cell line were generated by Goldring group. Human articular cartilage was obtained from femoral heads of five OA patients. Cells were incubated with VA692 and celecoxib (1, 0.5 and 0.2mM) with interleukin (IL)-1b (5ng/ml) for 48hrs. The expression of inflammatory cytokines and anti-oxidant enzymes was evaluated by quantitative qRT-PCR, prostaglandins (PG)-E 2 release by ELISA. Apoptosis levels and ROS production were evaluated by flow cytometry. Proteins extracted by T/C-28a2 cell line was employed to carry out western blot analysis and the iTRAQ methodology. Statistical analysis was performed by ANOVA and Bonferroni multiple comparison tests. Results: IL-1b-stimulated chondrocytes showed a significant increase (p<0.001) of COX-2, IL-1b, IL-6, IL-8, superoxide dismutase (SOD)-2 and catalase (CAT) gene expression, as well as of PGE 2 levels in OA chondrocyte and in T/C-28a2 cell line. The tested drugs significantly counteracted the effect of IL-1b, with a better modulation by VA692 1mM in T/C-28a2 (p<0.01 for COX-2, IL-1b, IL-8, CAT; p<0.001 for IL-6, SOD-2 and PGE 2). Regarding apoptosis and mitochondrial superoxide anion production, the new drug was able to significantly reduce (p<0.05) their increase induced by IL-1b (p<0.05). Proteomic analysis led to the identification of 797 proteins in T/C-28a2 cell line, 123 of which were significantly modulated by VA692 in presence of IL-1b (p<0.001), while 34 were modulated by IL-1b alone (p<0.05). 21 proteins were commonly modulated by the two groups, indicating that 101 proteins were regulated by VA692 in a specific manner. Among the proteins downregulated by VA692, some with structural function were detected, responsible for cytoskeleton reorganization, as well as chaperones (heat shock proteins) and glycolitic enzymes. Proteins involved in calcium metabolism and in ribosome biogenesis resulted up-regulated instead, as well as SOD-2 as confirmed by western blot analysis. Conclusions: Our data demonstrated the anti-inflammatory effect of VA692, suggesting also its anti-apoptotic and anti-oxidant role. The proteomic analysis demonstrated that VA692 induced not only an antiinflammatory regulation in chondrocytes but, interestingly, seemed to regulate their anabolic response. On the basis of our results, we can hypothesize that VA692 could present any advantages over other COX-2 inhibitors already available for therapeutic use. However, further in vitro and in vivo experiments are necessary to elucidate and confirm the importance of this pharmacological compound before its use in the therapeutic approach of joint diseases.

p ¼< 0.000 and p ¼< 0.000 and in total WOMAC score, p ¼< 0.000 and p ¼< 0.000) over TA group. Primary efficacy end point outcome (improvement ! 40%) of total WOMAC scores at 12 weeks, in Hylan G-F 20 and TA groups respectively was 30 (66.7%) and 5 (13.2%) in target knee joints (p ¼< 0.00) and at 26 weeks 35 (77.8%) and 10 (26.3%) in target knee joints (p ¼< 0.001). Within the group, VAS for pain reduction reported by patients and the investigator were significant statistically both at 12 and 26 weeks and in between groups, at weeks 12 (patient, p ¼ 0.002; investigator, p ¼ 0.001) and at weeks 26 (patient, p ¼ 0.000; investigator, p ¼ 0.000) respectively. Joint space improvement was also significant both at12 weeks (p ¼ 0.044) and 26 weeks (p ¼ 0.003) for Hylan G-F 20 than TA. Conclusions: A significant pain reduction, improvement in joint rheology and quality of life was observed with use of high molecular weight visco-supplementation (Hylan G-F 20) in patients suffering from primary knee OA refractory to standard care. Besides comparable efficacy both agents were found safe. Large scale project with longer follow up might answer long term outcomes.

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