Reframing Osteoarthritis: Beyond “Wear and Tear”

Osteoarthritis (OA) is a debilitating, prevalent condition whose heterogeneity is often underappreciated. Efforts to address this heterogeneity led to phenotyping (based on clinical observation) and endotyping (based on pathological mechanism) of OA. Steadily, perception of OA has changed from a ‘mechanical’ perspective to a ‘multi-endotype/ phenotype’ perspective with the rapid advent of omics strategies.

Adipose Tissue as an Endocrine Organ

Adipose tissue secretes several hormones including leptin, adiponectin and visfatin, which exert modulatory effects on the immune system and musculoskeletal system. Leptin is well-studied in OA with its effects on chondrocytes, synoviocytes and osteoblasts. The mechanisms of leptin are due to its structural homology to pro-inflammatory cytokines and direct intracellular signaling through its receptor ObR to cause decreased chondrocyte proliferation, increased osteoblast proliferation and various pro-inflammatory actions. Also, elevated leptin levels within the infrapatellar fat pad potentiate chondrocyte senescence and skew differentiation away from repair. Plasma and synovial fluid leptin have directly correlated with radiographic severity, levels of proinflammatory cytokines, MMP-1 and MMP-3. High resolution 3D MR images show correlation of leptin and soluble ObR levels with greater cartilage volume loss. Other hormones including adiponectin and visfatin promote osteoblast proliferation, osteoclast differentiation and enhance secretion of matrix metalloproteinases. Adiponectin exerts dual roles in cartilage homeostasis engaging AMP kinase and MAP kinase pathways. Resistin levels have been found to consistently vary with changes in leptin levels, underlining a crosstalk between the adipokines.

Obesity Beyond Mechanical Load

Dysregulated lipid metabolism and adipokine signaling play a central role in extracellular matrix degradation, bone and joint inflammation. Animal studies suggest that altered lipid metabolism/ efflux receptors (liver X receptor (LXR), peroxisome proliferator-activated receptor (PPAR) and retinoic acid-related orphan receptor α (RORα)) in chondrocytes can activate inflammatory pathways and favour cartilage destruction. Targeting these mediators of lipid metabolism or efflux has shown to reduce inflammation and prevent cartilage degradation.

The Metabolic Phenotype of Osteoarthritis

The metabolic syndrome phenotype of OA was proposed amongst other phenotypes in a systematic review of OA phenotypes published in 2016. Although different OA subgroups show varied trajectories of clinical progression, high BMI (body mass index) has consistently been a baseline factor that predicts worse clinical outcomes.

Clinical Implications in Practice

Semaglutide has shown to exhibit significant reduction of pain and body weight in moderate-to-severe OA in a 68-week, double-blind, placebo-controlled randomized trial. AMPK activators such as metformin, resveratrol have demonstrated considerable therapeutic potential in reducing synovial and chondrocyte inflammation. The findings further strengthen the case for current drugs that target metabolic pathways to be repurposed for preventing and treating cartilage degradation.

Therapeutic Opportunities and Unmet Needs

Synergistic targeting of inflammation and metabolism remains the next frontier which directly targets the root pathological mechanism in OA. There is a need for precision medicine to take over this lacunae and fulfil the need for lasting cure in OA

Key Take-Home Messages

• The perception of Osteoarthritis has shifted from simple “wear and tear” to a complex, multi-endotype condition where adipose tissue acts as an endocrine organ.

• Since metabolic dysfunction is a core driver of joint damage, there is significant potential in repurposing metabolic drugs for OA treatment.

 Suggested readings:

1. Deveza LA, Nelson AE, Loeser RF. Phenotypes of osteoarthritis: current state and future implications. Clin Exp Rheumatol. 2019 Sep-Oct;37 Suppl 120(5):64-72.

2. Azamar-Llamas D, Hernández-Molina G, Ramos-Ávalos B, Furuzawa-Carballeda J. Adipokine Contribution to the Pathogenesis of Osteoarthritis. Mediators Inflamm. 2017;2017:5468023.

3. Xiang Q, Wu Z, Zhao Y, Tian S, Lin J, Wang L, Jiang S, Sun Z, Li W. Cellular and molecular mechanisms underlying obesity in degenerative spine and joint diseases. Bone research. 2024 Dec 11;12(1):71.