## Enzymatic Degradation in Osteoarthritis **Key Point:** Matrix metalloproteinases (MMPs) are the primary enzymes responsible for breaking down the extracellular matrix components of articular cartilage in osteoarthritis. ### Role of MMPs in OA Pathogenesis **High-Yield:** The pathogenesis of OA involves an imbalance between: - **Cartilage-degrading enzymes** (MMPs, ADAMTS) — upregulated - **Tissue inhibitors of metalloproteinases (TIMPs)** — downregulated ### Key MMPs in Osteoarthritis | MMP | Substrate | Role in OA | |-----|-----------|----------| | **MMP-1 (Collagenase-1)** | Type I, II, III collagen | Degrades fibrillar collagen | | **MMP-13 (Collagenase-3)** | Type II collagen (primary) | Most important in cartilage breakdown | | **MMP-2 (Gelatinase A)** | Gelatin, collagen IV | Degrades denatured collagen | | **MMP-9 (Gelatinase B)** | Collagen IV, gelatin | Involved in matrix remodeling | **Mnemonic:** **ADAMTS** = A Disintegrin And Metalloproteinase with Thrombospondin motifs. These enzymes (especially ADAMTS-4 and ADAMTS-5) also degrade aggrecan, a critical cartilage proteoglycan. ### Cartilage Matrix Composition The cartilage matrix consists of: 1. **Type II collagen** — primary structural protein (degraded by MMP-13, MMP-1) 2. **Aggrecan** — proteoglycan providing compressive strength (degraded by ADAMTS) 3. **Other proteoglycans** — decorin, biglycan **Clinical Pearl:** MMP-13 is considered the "master enzyme" in OA because it specifically targets type II collagen, the predominant collagen in articular cartilage. Elevated MMP-13 levels correlate with cartilage degradation severity. ### Regulation in OA In osteoarthritis, chondrocytes are activated by: - Mechanical stress - Pro-inflammatory cytokines (IL-1β, TNF-α) - Growth factors (TGF-β) This leads to: 1. ↑ MMP expression (especially MMP-13) 2. ↓ TIMP expression 3. Net result: cartilage matrix degradation [cite:Robbins 10e Ch 26] 
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