Explore the vast range of titles available.

Osteoarthritis (OA) is a prevalent and severely debilitating disease with an unmet medical need. In order to alleviate OA symptoms or prevent structural progression of OA, new drugs, particularly disease-modifying osteoarthritis drugs (DMOADs), are required. Several drugs have been reported to attenuate cartilage loss or reduce subchondral bone lesions in OA and thus potentially be DMOADs. Most biologics (including interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibitors), sprifermin, and bisphosphonates failed to yield satisfactory results when treating OA. OA clinical heterogeneity is one of the primary reasons for the failure of these clinical trials, which can require different therapeutic approaches based on different phenotypes. This review describes the latest insights into the development of DMOADs. We summarize in this review the efficacy and safety profiles of various DMOADs targeting cartilage, synovitis, and subchondral bone endotypes in phase 2 and 3 clinical trials. To conclude, we summarize the reasons for clinical trial failures in OA and suggest possible solutions.

Background There is emerging evidence that the development and progression of osteoarthritis (OA) is associated with inflammation. C reactive protein (CRP), a systemic marker for inflammation, may be elevated in OA patients but the evidence is conflicting. Objective To systematically review the literature for the relationship between serum CRP levels measured by a high sensitivity method (high sensitive CRP (hs-CRP)) and OA, as well as the correlation between circulating CRP levels and OA phenotypes. Methods MEDLINE, EMBASE and CINAHL databases were systematically searched from January 1992 to December 2012. Studies were included when they met the inclusion criteria and data from studies were extracted. Two independent reviewers assessed study quality using a modified Newcastle-Ottawa Quality Assessment Scale. Meta-analyses were performed to pool available data from included studies. Results 32 studies met the inclusion criteria. Serum hs-CRP levels in OA were modestly but statistically significantly higher than controls (mean difference=1.19 mg/L, 95% CI 0.64 to 1.73, p<0.001) with significant heterogeneity between studies. Levels were significantly associated with pain (r=0.14, 95% CI 0.09 to 0.20, p<0.001) and decreased physical function (r=0.25, 95% CI 0.13 to 0.39, p<0.001). No significant associations were found between hs-CRP levels and radiographic OA. Conclusions Low-grade systemic inflammation may play a greater role in symptoms rather than radiographic changes in OA.

Osteoarthritis (OA) is the leading cause of function loss and disability among the elderly, with significant burden on the individual and society. It is a severe disease for its high disability rates, morbidity, costs, and increased mortality. Multifactorial etiologies contribute to the occurrence and development of OA. The heterogeneous condition poses a challenge for the development of effective treatment for OA; however, emerging treatments are promising to bring benefits for OA management in the future. This narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief. This review will focus more on drugs that have been in clinical trials, as well as attractive drugs with potential applications in preclinical research. In the past few years, it has been realized that a complex interaction of multifactorial mechanisms is involved in the pathophysiology of OA. The authors believe there is no miracle therapeutic strategy fitting for all patients. OA phenotyping would be helpful for therapy selection. A variety of potential therapeutics targeting inflammation mechanisms, cellular senescence, cartilage metabolism, subchondral bone remodeling, and the peripheral nociceptive pathways are expected to reshape the landscape of OA treatment over the next few years. Precise randomized controlled trials (RCTs) are expected to identify the safety and efficacy of novel therapies targeting specific mechanisms in OA patients with specific phenotypes.

Inflammatory cytokines-induced activation of the nuclear factor κB (NF-κB) pathway plays a critical role in the pathogenesis of osteoarthritis (OA). Circular RNA (circRNA) has been identified as important epigenetic factor in numerous diseases. However, the biological roles of inflammation-related circRNAs in regulating OA pathogenesis remain elusive. Here, we revealed circRNA expression profiles in human primary chondrocytes with interleukin-1β (IL-1β) stimulation by circRNA sequencing. We identified a highly upregulated circRNA, termed as circNFKB1 in inflamed chondrocytes and osteoarthritic cartilage. As a circRNA derived from exon 2–5 of NFKB1, circNFKB1 is located in both cytoplasm and nucleus of chondrocytes. Furthermore, knockdown of circNFKB1 inhibited extracellular matrix (ECM) catabolism and rescued IL-1β impaired ECM anabolism whereas ectopic expression of circNFKB1 significantly promoted chondrocytes degradation in vitro. Moreover, intraarticular injection of adenovirus-circNFKB1 in mouse joints triggered spontaneous cartilage loss and OA development. Mechanistically, circNFKB1 interacted with α-enolase (ENO1), regulated the expression of its parental gene NFKB1 and sustained the activation of NF-κB signaling pathway in chondrocytes. Therefore, this study highlights a novel ENO1-interacting circNFKB1 in OA pathogenesis, and provides valuable insights into understanding the regulatory mechanism of NF-κB signaling in chondrocytes and a promising therapeutic target for the treatment of OA.

Utilization of joint-resident mesenchymal stem cells (MSC) to repair articular cartilage is a promising strategy in osteoarthritis (OA) therapy but remains a considerable research challenge. Here, hierarchical targeting and microenvironment responsive peptide functionalized nanoparticles (NPs) are used to achieve cartilage repair in situ. Ultrasmall copper oxide (CuO) NPs are conjugated with type 2 collagen and MSC dual-targeting peptide (designated WPV) with a matrix metalloproteinase 2 (MMP-2)-sensitive sequence as a spacer to achieve hierarchical targeting. Guided by this peptide, WPV-CuO NPs initially penetrate cartilage and subsequently expose the inner MSC-targeted peptide to attract MSCs through MMP-2 clearance. CuO further promotes chondrogenesis of MSCs. In an anterior cruciate ligament transection rat model, intraarticular injection of WPV-CuO NPs induces significant reduction of cartilage destruction. The therapeutic mechanism involves inhibition of the PI3K/AKT/mTOR pathway, as determined via transcriptome analysis. In conclusion, a novel therapeutic strategy for OA has been successfully developed based on localized MSC recruitment and cartilage repair without transplantation of exogenous cells or growth factors. Graphical Abstract

Objective To determine the association between inflammatory markers and change in knee pain over 5 years. Methods A total of 149 randomly selected subjects (mean 63 years, range 52–78; 46% female) was studied. Serum levels of high sensitivity C-reactive protein (hs-CRP), tumour necrosis factor alpha (TNF–α) and interleukin (IL)-6 were measured at baseline and 2.7 years later. Knee pain was recorded using the Western Ontario and McMasters osteoarthritis index questionnaire at baseline and 5 years later. Knee radiographic osteoarthritis of both knees was assessed at baseline, and knee bone marrow lesions, joint effusion and cartilage defects were determined using T1 or T2-weighted fat saturated MRI. Results After adjustment for confounding variables, baseline hs-CRP was positively associated with change in total knee pain (β=0.33 per mg/l, p=0.032), as well as change in the pain at night in bed (β=0.12 per ml/pg, p=0.010) and while sitting/lying (β=0.12 per ml/pg, p=0.002). Change in hs-CRP was also associated with change in knee pain at night and when sitting/lying (both p<0.05). Baseline TNFα and IL-6 were associated with change in pain while standing (β=0.06 per ml/pg, p=0.033; β=0.16 per ml/pg, p=0.035, respectively), and change in TNFα was positively associated with change in total knee pain (β=0.66 ml/pg, p=0.020) and change in pain while standing (β=0.26 ml/pg, p=0.002). Adjustment for radiographic osteoarthritis or MRI-detected structural abnormalities led to no or minor attenuation of these associations. Conclusion Systemic inflammation is an independent predictor of worsening knee pain over 5 years.

Objective To investigate the causal relationship between low bone mineral density (BMD) and osteoarthritis (OA) using Mendelian randomization (MR) design. Methods Two-sample bi-directional MR analyses were performed using summary-level information on OA traits from UK Biobank and arcOGEN. Sensitivity analyses including MR-Egger, simple median, weighted median, MR pleiotropy residual sum, and outlier approaches were utilized in conjunction with inverse variance weighting (IVW). Gene ontology (GO) enrichment analyses and expression quantitative trait locus (eQTL) colocalization analyses were used to investigate the potential mechanism and shared genes between osteoporosis (OP) and OA. Results The IVW method revealed that genetically predicted low femoral neck BMD was significantly linked with hip ( β  = 0.105, 95% CI: 0.023–0.188) and knee OA ( β  = 0.117, 95% CI: 0.049–0.184), but not with other site-specific OA. Genetically predicted low lumber spine BMD was significantly associated with OA at any sites ( β  = 0.048, 95% CI: 0.011–0.085), knee OA ( β  = 0.101, 95% CI: 0.045–0.156), and hip OA ( β  = 0.150, 95% CI: 0.077–0.224). Only hip OA was significantly linked with genetically predicted reduced total bone BMD ( β  = 0.092, 95% CI: 0.010–0.174). In the reverse MR analyses, no evidence for a causal effect of OA on BMD was found. GO enrichment analysis and eQTL analysis illustrated that DDN and SMAD-3 were the most prominent co-located genes. Conclusions These findings suggested that OP may be causally linked to an increased risk of OA, indicating that measures to raise BMD may be effective in preventing OA. More research is required to determine the underlying processes via which OP causes OA.

BackgroundThe infrapatellar fat pad (IPFP) is of uncertain significance for knee osteoarthritis. The aim of this study was to describe the longitudinal associations between baseline IPFP maximal area and changes in knee pain, knee cartilage volume and cartilage defects in older adults.Methods356 community-dwelling male and female adults aged 50–80 years were measured at baseline and approximately 2.6 years later. T1-weighted or T2-weighted fat-suppressed MRI was used to assess maximal IPFP area, cartilage volume and cartilage defects at baseline and/or follow-up. Knee pain was assessed by the self-administered Western Ontario McMaster Osteoarthritis Index questionnaire.ResultsAfter adjustment for confounders, IPFP maximal area in women was significantly and negatively associated with changes in knee pain (β: −0.18 to −0.86 for total knee pain, pain at night while in bed, pain when sitting/lying and pain when standing upright, all p<0.05) but not with other knee pain subscales. IPFP maximal area in women was beneficially associated with change in tibial cartilage volume per annum (β: +1.56% per cm2 at medial site; +0.86% per cm2 at lateral site, both p<0.05), but not with change in patellar cartilage volume. Further, it was significantly associated with reduced risks of increases in medial cartilage defects (relative risk: 0·46 at tibial site, relative risk: 0.59 at femoral site; both p<0.05) but not with increases at other sites in women. No significant associations were found in men.ConclusionsWhile the associations are not fully consistent, IPFP maximal area appears to have a protective role for knee symptoms and cartilage damage in older female adults.

Background To describe demographic and clinical factors associated with the presence and incidence of depression and explore the temporal relationship between depression and joint symptoms in patients with symptomatic knee osteoarthritis (OA). Methods Three hundred ninety-seven participants were selected from a randomized controlled trial in people with symptomatic knee OA and vitamin D deficiency (age 63.3 ± 7.1 year, 48.6% female). Depression severity and knee joint symptoms were assessed using the patient health questionnaire (PHQ-9) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), respectively, at baseline and 24 months. Results The presence and incidence of depression was 25.4 and 11.2%, respectively. At baseline, having younger age, a higher body mass index (BMI), greater scores of WOMAC pain (PR: 1.05, 95%CI:1.03, 1.07), dysfunction (PR: 1.02, 95%CI:1.01, 1.02) and stiffness (PR: 1.05, 95%CI: 1.02, 1.09), lower education level, having more than one comorbidity and having two or more painful body sites were significantly associated with a higher presence of depression. Over 24 months, being female, having a higher WOMAC pain (RR: 1.05, 95%CI: 1.02, 1.09) and dysfunction score (RR: 1.02, 95%CI: 1.01, 1.03) at baseline and having two or more painful sites were significantly associated with a higher incidence of depression. In contrast, baseline depression was not associated with changes in knee joint symptoms over 24 months. Conclusion Knee OA risk factors and joint symptoms, along with co-existing multi-site pain are associated with the presence and development of depression. This suggests that managing common OA risk factors and joint symptoms may be important for prevention and treatment depression in patients with knee OA. Trial registration ClinicalTrials.gov identifier: NCT01176344 . Anzctr.org.au identifier: ACTRN12610000495022 .

Osteoarthritis (OA) is the commonest musculoskeletal disease worldwide, with an increasing prevalence due to aging. It causes joint pain and disability, decreased quality of life, and a huge burden on healthcare services for society. However, the current main diagnostic methods are not suitable for early diagnosing patients of OA. The use of machine learning (ML) in OA diagnosis has increased dramatically in the past few years. Hence, in this review article, we describe the research progress in the application of ML in the early diagnosis of OA, discuss the current trends and limitations of ML approaches, and propose future research priorities to apply the tools in the field of OA. Accurate ML-based predictive models with imaging techniques that are sensitive to early changes in OA ahead of the emergence of clinical features are expected to address the current dilemma. The diagnostic ability of the fusion model that combines multidimensional information makes patient-specific early diagnosis and prognosis estimation of OA possible in the future.