Osteoarthritis Pathophysiology

Osteoarthritis is a whole joint disease involving cartilage degradation, subchondral bone remodeling, osteophyte formation, synovial inflammation, and soft tissue changes—not simply "wear and tear" of cartilage. The fundamental pathology is an imbalance where catabolic pathways exceed anabolic capacity 3-5 times, driven by master inflammatory mediators IL-1β and TNF-α that upregulate destructive enzymes: MMP-13 (primary collagenase) and ADAMTS-4/5 (aggrecanases). Subchondral bone undergoes sclerosis with 40% volume increase, cyst formation, and bone marrow lesions (BMLs) that correlate with pain—these changes may precede or follow cartilage loss. Early OA shows paradoxically increased cartilage water content from proteoglycan loss, while senescent cells accumulate with pro-inflammatory SASP phenotype, driving progression even in the absence of acute inflammation. Currently, no disease-modifying OA drugs (DMOADs) have been approved.

Osteoarthritis (OA) was historically viewed as simple "wear and tear" of cartilage. The modern understanding recognizes OA as a complex, multifactorial disease of the entire joint organ, involving all tissues and driven by biomechanical and inflammatory mechanisms.

The paradigm shift from passive degeneration to active disease process emphasizes failed repair responses, where chondrocytes attempt regeneration but produce inferior matrix. This understanding has opened therapeutic avenues targeting inflammation, senescence, and metabolic pathways.

Core Pathophysiological Concepts

Central Paradigm: Failed Repair Response

OA represents a fundamental failure of joint homeostasis where catabolic processes overwhelm anabolic repair mechanisms. This creates a self-perpetuating cycle of degradation.

Key Molecular Imbalance:

• Catabolic mediators: IL-1beta, TNF-alpha, MMPs, ADAMTS
• Anabolic mediators: IGF-1, TGF-beta, BMPs
• Net result: 3-5x more degradation than synthesis

Tissue Crosstalk:

The whole joint disease concept emphasizes bidirectional communication between tissues:

• Cartilage degradation products activate synovial inflammation
• Synovial cytokines accelerate cartilage catabolism
• Subchondral bone changes alter mechanical loading on cartilage
• Osteophytes form as attempted stabilization

Early Changes

OA cartilage undergoes progressive structural and compositional changes beginning at molecular level before gross damage appears.

Compositional Changes:

• Water content: Increases from 70% to 80%+ (proteoglycan loss)
• Collagen content: Net loss despite repair attempts
• Collagen crosslinking: Altered (more immature crosslinks)
• Matrix organization: Disrupted fibrillar architecture

Catabolic Enzymes

Matrix degradation is mediated by specific proteases that are upregulated in OA chondrocytes.

IL-1beta Signaling Cascade:

1. IL-1beta binds IL-1R1 receptor
2. Recruits IL-1RAcP co-receptor
3. Activates MyD88 adapter protein
4. Triggers NF-kappaB and MAPK (p38, ERK, JNK) pathways
5. Nuclear translocation of transcription factors
6. Upregulation of MMP-13, ADAMTS-4/5, iNOS, COX-2
7. Downregulation of collagen II, aggrecan synthesis

Chondrocyte Phenotypic Changes

OA chondrocytes undergo phenotypic alterations attempting to repair damaged matrix but ultimately contributing to pathology.

Cell Clusters:

• Chondrocyte proliferation near damaged areas
• Attempt to synthesize new matrix
• Produce inferior quality (more type I collagen)
• Short-lived response - cells eventually undergo apoptosis
• Sign of failed repair attempt

Hypertrophic Differentiation:

• Expression of type X collagen (normally only in growth plate)
• Upregulation of MMP-13, VEGF, RUNX2
• Promotes calcification and vascular invasion
• Recapitulates endochondral ossification program
• Contributes to osteophyte formation

Senescence:

• Accumulation of senescent cells with aging and OA
• Senescence-associated secretory phenotype (SASP)
• SASP includes IL-6, IL-8, MMPs, growth factors
• Drives chronic inflammation
• Target for senolytics (drugs clearing senescent cells)

Bone Remodeling

Subchondral bone undergoes dramatic changes in OA, with active remodeling that may precede or accelerate cartilage loss.

Early Bone Changes:

• Increased bone turnover markers (CTX-I, NTX-I)
• Trabecular thickening (40% volume increase)
• Altered bone mineralization density
• Microdamage and microcracks

Advanced Bone Changes:

• Sclerosis visible on radiographs
• Subchondral cysts (geodes)
• Bone marrow lesions on MRI
• Osteophyte formation at margins

Chicken or Egg Debate: Does subchondral bone pathology cause cartilage loss, or vice versa? Evidence suggests bidirectional relationship with both contributing to progression.

Bone Marrow Lesions (BMLs)

BMLs are areas of high signal intensity on T2-weighted or STIR MRI sequences, representing bone marrow edema, microfracture, ischemia, or necrosis.

Clinical Significance:

• Strong correlation with knee pain severity
• Predict risk of cartilage loss progression
• Fluctuate over time (unlike structural damage)
• May respond to bone-targeted therapies

Treatment Implications:

• Bisphosphonates may reduce BML size and pain
• Unloading (e.g., valgus brace for medial BMLs) may help
• Targeting bone may be as important as targeting cartilage

Low-Grade Synovitis

OA synovium exhibits chronic low-grade inflammation distinct from rheumatoid arthritis but still contributing to symptoms and progression.

Inflammatory Features:

• Synovial hyperplasia (2-3x normal thickness)
• Infiltration of macrophages and lymphocytes
• Increased vascularity
• Elevated inflammatory mediators (IL-1, TNF, IL-6)

Synovial Membrane Changes:

• Lining layer hyperplasia (normally 1-2 cells thick, becomes 4-10)
• Sublining fibrosis and inflammation
• Release of matrix fragments (wear particles)
• Activation of complement cascade

Inflammatory Mediators Released:

• Cytokines: IL-1beta, TNF-alpha, IL-6, IL-8
• Chemokines: MCP-1, RANTES
• Growth factors: VEGF, NGF (nerve growth factor)
• Enzymes: MMPs, ADAMTS, hyaluronidase

Complement Activation

The complement system, classically associated with immune responses, is activated in OA synovium and contributes to tissue damage.

Activation Pathways:

• Alternative pathway triggered by cartilage degradation products
• C5a and membrane attack complex (MAC) formation
• Amplifies inflammatory response
• Contributes to synovial and cartilage damage

Therapeutic Target: Complement inhibitors are being investigated as potential DMOADs.

Current Therapeutic Landscape

No disease-modifying OA drugs (DMOADs) have been approved despite extensive research. Current treatments are symptomatic.

Symptomatic Treatments:

• NSAIDs: COX-2 inhibition reduces pain, doesn't slow progression
• Viscosupplementation: Hyaluronic acid - modest short-term benefit
• Corticosteroid injection: Anti-inflammatory, temporary relief
• Analgesics: Acetaminophen, tramadol for pain

Investigational DMOADs:

• Anti-NGF antibodies: Reduced pain but safety concerns (joint damage, fractures)
• FGF-18 (sprifermin): Early promise for cartilage regeneration
• Wnt pathway inhibitors: Target aberrant signaling
• Senolytics: Clear senescent cells

Emerging Concepts

Metabolic OA: Recognition that obesity contributes via metabolic mechanisms (adipokines, inflammation) not just mechanical overload. Leptin, adiponectin, resistin from adipose tissue promote OA.

Genetic Factors: GWAS studies identify OA susceptibility loci (GDF5, COL11A1, SMAD3). Genetic risk scores may predict progression and guide personalized therapies.

Microbiome: Emerging evidence that gut microbiome influences OA via systemic inflammation. Dysbiosis may contribute to disease.

Australian Epidemiology and Practice

Osteoarthritis Burden in Australia:

• Approximately 2.2 million Australians affected by osteoarthritis
• OA accounts for over 50% of all joint replacements in Australia (AOANJRR data)
• Leading cause of disability and pain in Australians over 45 years
• Economic burden exceeds $3.5 billion annually including healthcare costs and lost productivity

RACS Orthopaedic Training Relevance:

• OA pathophysiology is core FRACS Basic Science examination content
• Understanding IL-1beta, MMP-13, ADAMTS pathways frequently examined
• Subchondral bone changes and BML concept are viva topics
• Molecular basis informs arthroplasty decision-making

Australian Research Contributions:

• Australian centres contribute significantly to OA research including the Melbourne Collaborative Cohort Study
• Monash University leads research into senolytics and novel therapeutics
• OARSI (Osteoarthritis Research Society International) guidelines followed in Australia

PBS Considerations:

• NSAIDs (celecoxib, meloxicam) PBS-listed for OA management
• Paracetamol and opioids PBS-subsidised for pain management
• Hyaluronic acid injections not PBS-listed but privately available
• Duloxetine PBS-listed for chronic pain including OA-related pain

eTG Recommendations:

• Conservative management first-line (weight loss, exercise, physiotherapy)
• Paracetamol as first-line analgesic; NSAIDs short-term with gastroprotection if required
• Intra-articular corticosteroid for symptom flares
• Arthroscopy not recommended for treatment of OA (per RACGP guidelines)

Clinical Practice Guidelines:

• RACGP Guideline for OA management in primary care
• Arthritis Australia patient education resources
• Musculoskeletal Australia (MSK) support services