Post-traumatic knee osteoarthritis; the role of inflammation and hemarthrosis on disease progression

Abstract

Knee injuries such as anterior cruciate ligament ruptures and meniscal injury are common and are most frequently sustained by young and active individuals. Knee injuries will lead to post-traumatic osteoarthritis (PTOA) in 25-50% of patients. Mechanical processes where historically believed to cause cartilage breakdown in PTOA patients. But there is increasing evidence suggesting a key role for inflammation in PTOA development. Inflammation in PTOA might be aggravated by hemarthrosis which frequently occurs in injured knees. Whereas mechanical symptoms (joint instability and locking of the knee) can be successfully treated by surgery, there still is an unmet need for anti-inflammatory therapies that prevent PTOA progression. In order to develop anti-inflammatory therapies for PTOA, more knowledge about the exact pathophysiological mechanisms and exact course of post-traumatic inflammation is needed to determine possible targets and timing of future therapies.

Keywords: hemarthrosis; inflammation; knee injuries; post-traumatic knee osteoarthritis; synovitis.

Figure 1

Schematic overview of pathophysiology in PTOA. 1: Direct impact from trauma higher than 10–20 MPa results in necrotic cell death of chondrocytes and damage to the ECM of the cartilage. 2: A spatial shift due to increased joint laxity after ligament rupture causes a change in load bearing contact area. This leads to fibrillation of the collagen network and when fractured, these fibrils act as DAMPs. 3: DAMPs (e.g., glycoproteins proteoglycans, or GAG) are released into the articular cavity as result of acute traumatic cartilage damage. 4: DAMPs bind to pattern recognition receptors (TLRs, NLRs, and RAGE) on the surface of immune cells, chondrocytes, osteoblasts (not shown here), macrophages and fibroblasts. 5: activated cells release inflammatory cytokines such as IL-1, IL-4, IL-6, IL-8, IL-10, IL-17, TNF-α, chemokines, cathepsins, complement cascade factors, and DAMPs [e.g., S-100 proteins, high-mobility group box protein 1 (HMGB1), or uric acid]. 6: Inflammatory factors promote release of MMPs and ADAMTS by synoviocytes and chondrocytes which leads to cartilage degradation. 7: Major peri-articular tissue damage (e.g., anterior cruciate ligament rupture) causes hemarthrosis. Degradation of erythrocytes causes the release of heme-derived iron molecules. 8: Heme-derived iron molecules react with oxygen metabolites generated by monocytes and macrophages forming hydroxyl radicals. 9: hydroxyl radicals induce chondrocyte apoptosis and therefore promote cartilage damage1. 10: Synovial inflammation is induced by DAMPs, pro-inflammatory factors and hemosiderin deposits in the synovium formed by the accumulation of iron molecules. 11: Synovial inflammation is characterized by influx of immune cells. 12: Cells in the inflamed synovium release cytokines, DAMPs and promote release of MMPs leading to cartilage breakdown which again promotes the release of DAMPs into the joint cavity. MPa, millipascal; ECM, extracellular matrix; DAMP, damage-associated molecular pattern; GAG, glycoproteins and glycosaminoglycans; TLRs, Toll-like receptors; NLRs, NOD-like receptors; RAGE, receptor for advanced glycation end-products; IL, interleukin; MMPs, matrix metalloproteinases; ADAMTS 9, a disintegrin and metalloproteinase with thrombospondin motifs.