Metabolic dysregulation in osteoarthritis: mechanisms and targeted therapeutic strategies

Abstract

BACKGROUND: Osteoarthritis has traditionally been considered as a degenerative joint disorder, with the central role of metabolic dysregulation in its pathogenesis long overlooked. Recent studies reveal a strong association between metabolic syndromes, such as obesity and diabetes, and osteoarthritis progression, yet the molecular mechanisms by which metabolic dysregulation results in joint degeneration remain poorly elucidated. OBJECTIVE: To systematically review advances in the pathological mechanisms of metabolic dysregulation in osteoarthritis, integrating multi-omics evidence to decode the regulatory network of the "metabolism-joint axis," and to provide novel perspectives for the clinical prevention and treatment of metabolic dysregulation in osteoarthritis. METHODS: An online search of the China National Knowledge Infrastructure and Wanfang databases was conducted using the terms "osteoarthritis, metabolic dysregulation, adipokine, glycolysis, mitochondrial dysfunction, metabolomics, MRI" in Chinese to retrieve relevant literature. Additionally, PubMed and Web of Science were searched using the English terms "osteoarthritis, metabolic dysregulation, adipokine, glycolysis, mitochondrial dysfunction, metabolomics, MRI." After screening titles and abstracts, as well as evaluating full texts, 108 articles were finally included for review. RESULTS AND CONCLUSION: Epidemiological studies confirm that metabolic syndrome (obesity, diabetes, dyslipidemia) is positively correlated with osteoarthritis risk; each 1 kg/m2 increase in body mass index raises the risk of knee osteoarthritis by 15%, and involvement of non-weight-bearing joints supports the independent pathogenic role of metabolic factors. Imbalance of the adipokine network drives osteoarthritis progression: obesity leads to abnormal leptin/adiponectin ratio (leptin increased 3.2-fold, adiponectin decreased 40%), which accelerates cartilage degradation by activating matrix metalloproteinase 13 (increased 2.1-fold) and inhibiting tissue inhibitor of metalloproteinase 2. Intracellular metabolic reprogramming is prominent: osteoarthritic chondrocytes exhibit a triad of enhanced glycolysis, mitochondrial dysfunction, and lipid droplet deposition (free fatty acids increased 1.8-fold). A metabolic-inflammatory positive feedback loop: adipose tissue releases interleukin-1β/tumor necrosis factor-α to activate the nuclear factor-κB pathway in joints, which in turn inhibits insulin receptor signaling and exacerbates metabolic disturbance. Clinical translation: serum adiponectin combined with synovial fluid lactate can predict osteoarthritis progression; early use of AMP-activated protein kinase agonists combined with muscle training and nutritional intervention is recommended for patients with metabolic syndrome.

1. Introduction

Osteoarthritis (OA) is the most common degenerative joint disease [1-2]. With the aging population, the global burden of OA is projected to increase by more than 50% by 2040 [3]. Traditionally, OA has been viewed as a local disease driven by mechanical stress, with clinical treatment focusing on symptom relief and end-stage joint replacement, lacking effective disease-modifying drugs [4]. This therapeutic gap stems from a limited understanding of OA pathogenesis—the mechanical wear theory cannot explain the increased risk of OA in non-weight-bearing joints (e.g., hands) in obese patients, nor can it clarify the molecular drivers of early-onset OA [4-5].

Recent research has revealed that metabolic dysregulation is an independent driver of OA progression [6]. A large cohort study (n=1,764,061) showed that obese individuals have a 3.05-fold higher risk of knee OA (95% CI: 2.78-3.35), which remains significant after adjusting for mechanical load [7]. Metabolic syndrome (obesity, insulin resistance, dyslipidemia) shares comorbid mechanisms with OA: adipose tissue releases adipokines such as leptin and resistin, as well as pro-inflammatory cytokines like tumor necrosis factor-α and interleukin-1β, which act systemically on joint tissues to accelerate cartilage degradation [8].

This review systematically integrates recent breakthroughs in OA metabolic mechanisms, from adipokine dysregulation and intracellular metabolic reprogramming (enhanced glycolysis/mitochondrial dysfunction) to the gut-joint axis, combined with biomarker screening and multi-omics analysis. It elucidates the scientific basis for metabolic subtype classification and evaluates the clinical translation potential of traditional drugs such as metformin and statins, as well as novel therapies like ursodeoxycholic acid and glucagon-like peptide-1 receptor agonists. By integrating cross-disciplinary evidence, this review aims to promote a paradigm shift in OA management from symptomatic treatment to etiological intervention, providing a theoretical foundation for the development of metabolic-targeted disease-modifying drugs.