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Osteoarthritis (OA) is characterized by the dysregulation of the osteochondral interface between bone and cartilage. In vitro, osteochondral models are crucial for studying OA and testing treatments. However, current models are limited to replicating the extracellular matrix's structural and mechanical heterogeneity and do not account for the distinct oxygen gradients that chondrocytes and osteoblasts experience at the osteochondral interface. By using micropatterned granular hydrogels to control oxygen scavenging agents' delivery, maintaining <1% oxygen concentration in standard cell culture conditions. These hypoxic hydrogels allow primary human chondrocytes to exhibit a more anabolic phenotype, akin to hypoxic incubator conditions. Patterning of the hydrogels in a microfluidic device creates localized hypoxic environments that mimic the osteochondral interface, enabling co‐culture of chondrocytes with osteoblasts from non‐sclerotic and sclerotic subchondral bone. This co‐culture in differential oxygen conditions revealed that sclerotic osteoblasts induce collagen expression changes in chondrocytes through MMP13 and ADAM15 production, a phenomenon not observed in uniform oxygen environments. Additionally, this model uncovered extensive transcriptional changes involving NF‐κβ, TGF‐β/BMP, and IGF signaling pathways, induced by sclerotic osteoblasts, which are undetectable in normoxic co‐cultures. The microfluidic model with localized oxygen variations effectively simulates osteoblast‐chondrocyte interactions, offering significant insights into OA pathophysiology. [ABSTRACT FROM AUTHOR]

Aims: Increasing evidence suggests that metformin can affect bone metabolism beyond its hypoglycemic effects in diabetic patients. However, the effects of metformin on fracture risk in type 2 diabetes mellitus (T2DM) patients remain unclear. A systematic review and meta-analysis were performed in this study to evaluate the association between metformin application and fracture risk in T2DM patients based on previous studies published until June 2021. Methods: A systematic search was performed to collect publications on metformin application in T2DM patients based on PubMed, Embase, Cochran, and Web of Science databases. Meta-analysis was performed by using a random-effects model to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). Subgroup analyses based on cohort/casecontrol and ethnicity and sensitivity analyses were also performed. Results: Eleven studies were included in the meta-analysis. Results demonstrated metformin use was not significantly associated with a decreased risk of fracture (RR, 0.91; 95% CI, 0.81-1.02; I² = 96.8%). Moreover, metformin use also demonstrated similar results in subgroup analyses of seven cohort studies and four case-control studies, respectively (RR, 0.90; 95% CI, 0.76-1.07; I² = 98.0%; RR, 0.96; 96% CI, 0.89-1.03; I² = 53.7%). Sensitivity analysis revealed that there was no publication bias. Conclusion: There was no significant correlation between fracture risk and metformin application in T2DM patients. Due to a limited number of existing studies, further research is needed to make a definite conclusion for clinical consensus. [ABSTRACT FROM AUTHOR]

Objective: Chronic inflammation plays an important role in the osteoarthritis (OA) pathology but how this influence OA disease progression is unclear. Leukotriene B4 (LTB 4 ) is a potent proinflammatory lipid mediator generated from arachidonic acid through the sequential activities of 5-lipoxygenase, 5-lipoxygenase-activating protein, Leukotriene A 4 hydrolase (LTA 4 H) and its downstream product LTB 4 . The aim of this study is to investigate the involvement and the potential therapeutic target of the LTB 4 pathway in OA disease progression., Design: Both clinical human cartilage samples ( n = 7) and mice experimental OA models ( n = 6) were used. The levels of LTA 4 H and leukotriene B4 receptor 1 were first examined using immunostaining in human OA/non-OA cartilage and mice experimental OA models. We also determined whether the LTA 4 H pathway was associated with cartilage degeneration and synovitis inflammation in OA mice models and human articular chondrocytes., Results: We found that both LTA 4 H and LTB 4 receptor (BLT1) were highly expressed in human and mice OA cartilage. Inhibition of LTA 4 H suppressed cartilage degeneration and synovitis in OA mice model. Furthermore, inhibition of LTA 4 H promoted cartilage regeneration by upregulating chondrogenic genes expression such as aggrecan ( ACAN ), collagen 2A1 ( COL2A1 ), and SRY-Box transcription factor 9 ( SOX9 )., Conclusions: Our results indicate that the LTA 4 H pathway is a crucial regulator of OA pathogenesis and suggest that LTA 4 H could be a therapeutic target in combat OA., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Osteoarthritis (OA) is a multifactorial joint disease with pathological changes that affect whole joint tissue. Obesity is acknowledged as the most influential risk factor for both the initiation and progression of OA in weight-bearing and non-weight-bearing joints. Obesity-induced OA is a newly defined phenotypic group in which chronic low-grade inflammation has a central role. Aside from persistent chronic inflammation, abnormal mechanical loading due to increased body weight on weight-bearing joints is accountable for the initiation and progression of obesity-induced OA. The current therapeutic approaches for OA are still evolving. Tissue-engineering-based strategy for cartilage regeneration is one of the most promising treatment breakthroughs in recent years. However, patients with obesity-induced OA are often excluded from cartilage repair attempts due to the abnormal mechanical demands, altered biomechanical and biochemical activities of cells, persistent chronic inflammation, and other obesity-associated factors. With the alarming increase in the number of obese populations globally, the need for an innovative therapeutic approach that could effectively repair and restore the damaged synovial joints is of significant importance for this sub-population of patients. In this review, we discuss the involvement of the systemic and localized inflammatory response in obesity-induced OA and the impact of altered mechanical loading on pathological changes in the synovial joint. Moreover, we examine the current strategies in cartilage tissue engineering and address the critical challenges of cell-based therapies for OA. Besides, we provide examples of innovative ways and potential strategies to overcome the obstacles in the treatment of obesity-induced OA., The Translational Potential of This Article: Altogether, this review delivers insight into obesity-induced OA and offers future research direction on the creation of tissue engineering-based therapies for obesity-induced OA., Competing Interests: The authors have no conflicts of interest to disclose in relation to this article., (© 2020 The Authors.)

Exosomes are small endosome-derived lipid nanoparticles (50-120 nm in diameter), actively secreted by exocytosis in most living cells. Recently, there is a growing interest of research focused on studying the exosome functions and to understand ways to use them for therapeutic applications in a wide variety of disorders, such as cancer, cardiovascular, neurodegenerative, and musculoskeletal diseases. Recently, a number of techniques have been developed for the isolation of exosomes such as ultracentrifugation, micro-filtration centrifugation, gradient centrifugation, and size-exclusion chromatography. In this chapter, we reveal the protocol and key insights into the isolation, purification, and characterization of exosomes using ultracentrifugation method.