Osteoarthritis: pathogenic signaling pathways and therapeutic targets

Abstract

Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies.

PGC-1α in osteoarthritic chondrocytes: From mechanism to target of action

“…As an important regulator of energy homeostasis, AMPK responds to changes in the ratio of ATP to AMP by regulating metabolic enzymes to promote ATP production and inhibit ATP consumption ( Herzig and Shaw, 2018 ). AMPK is a recognized upstream regulator of PGC-1α, which can directly affect the activity of PGC-1α through phosphorylation ( Yao et al, 2023 ) ( Figure 1 ). Silent information regulator 1 (SIRT1) is a histone deacetylase that maintains cartilage homeostasis by promoting chondrocyte proliferation, differentiation and survival, and upregulating genes important for cartilage function ( Almeida and Porter, 2019 ).…”

“…In addition, SIRT3 also affects AMPK activity by promoting the expression of liver kinase B1 (LKB1) ( Li et al, 2022 ). LKB1 is the main kinase that catalyzes the process of AMPK activation and energy production, and the activation of AMPK further promotes the expression of PGC-1α ( Yao et al, 2023 ). Forkhead box class O 3 A (FoxO3A) is a transcription factor of the FOXO family, and like PGC-1α, limits cellular oxidative stress by upregulating antioxidant enzymes ( Zhao et al, 2014 ; Almeida and Porter, 2019 ).…”

Emerging roles ofRNAbinding proteins in intervertebral disc degeneration and osteoarthritis

“…The cellular metabolism in IVD and articular cartilage is a coordinated network dynamically modulated at various levels by external stimuli (environmental factors) and resource availability (genetic factors). Although the molecular mechanisms underlying cellular metabolism remain largely unclear, it is widely accepted that apoptosis, ECM disruption, inflammation, and angiogenesis are involved in the development of IDD and OA 8,41,54–56 . Moreover, studies have demonstrated that these biological processes mentioned above are closely associated with PTGR, which is coordianted by RBPs and ribonucleoprotein (RNP) complexes 10,11,13 .…”

Photodynamic therapy for arthritis: A promising therapeutic strategy

“…OA is a primary cause of disability that results in cartilage deterioration and joint remodeling. 43 Chronic mild inflammation significantly drives OA, with synovitis exacerbating symptoms, joint issues, and cartilage damage. 44 PDT is a low-invasive method for the treatment of OA with high efficacy and selectivity.…”