Molecular characterization of articular cartilage from young adults with femoroacetabular impingement.

Recent advances in understanding structural hip disease have bolstered the theory of secondary osteoarthritis1,2. In this model of hip osteoarthritis pathophysiology, joint degeneration is secondary to an abnormal mechanical environment commonly caused by femoroacetabular impingement. This impingement results from a distinct morphologic abnormality of the acetabular rim (pincer deformity) and/or the femoral head-neck junction (cam deformity). These structural malformations produce dynamic, repetitive abutment between the proximal aspect of the femur and the acetabular rim leading to labrochondral dissociation, articular cartilage detachment, and progressive joint degeneration3-5. In this model of secondary hip osteoarthritis, underlying structural abnormalities of the acetabulum and proximal aspect of the femur causing femoroacetabular impingement mediate progressive osteoarthritis and eventually hip joint failure1,4. Despite increasing knowledge regarding femoroacetabular impingement and secondary osteoarthritis, this theory remains controversial and the role of femoroacetabular impingement in the pathophysiology of osteoarthritis continues to be questioned6. Our understanding of the biology of osteoarthritis has expanded markedly in recent years. Current information indicates that articular cartilage degeneration, characteristic of osteoarthritis, is mediated by several distinct molecular mediators such as cytokines, chemokines, and metalloproteinases7 that are released by intra-articular and periarticular soft tissues (Table I). Cytokines are cell-signaling proteins produced by chondrocytes and synovial cells within the hip joint that act to stimulate inflammation and regulate extracellular matrix homeostasis7. Interleukin-1β (IL-1β) is a cytokine that strongly increases inflammation and is thought to play a pivotal role in both early and late-stage osteoarthritis8. IL-1β causes articular cartilage destruction in part by stimulating production of MMP (matrix metalloproteinase)-13 and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-4, the enzymes responsible for cleavage of the major structural proteins in the cartilage matrix (type-II collagen and aggrecan, respectively)9-11. Additionally, more recent investigations have implicated certain chemoattractive cytokines (chemokines) as potential mediators of articular cartilage degeneration12-15. Chemokines represent a large family of structurally related inflammatory and immune system mediators that may have important roles in normal articular cartilage physiology and disease states16,17. Chemokine production is upregulated by proinflammatory molecules such as IL-1β and tumor necrosis factor alpha (TNF-α), and chemokines may play a role in osteoarthritis by recruiting inflammatory cells to injured cartilage, by directly stimulating inflammation and production of degradative enzymes such as MMP-13, or by stimulating the death of chondrocytes through apoptosis16,18,19. TABLE I Candidate Genes Important in the Potential Biological Link Between Femoroacetabular Impingement and Secondary Osteoarthritis Despite our improved understanding of hip pathomechanics and osteoarthritis pathobiology, the cellular and molecular “links” between the pathologic mechanical environment and the metabolic alterations of articular cartilage in hip osteoarthritis are not understood. An improved understanding of these biologic cascades will facilitate future disease staging and therapeutic strategies for pre-arthritic and early arthritic hip disease. Nevertheless, characterization of the cellular and molecular events that mediate articular cartilage degeneration remains problematic because of the current limitations of animal models of hip osteoarthritis, the questionable relevance of in vitro osteoarthritis models, and the inherent limitations in obtaining and studying human cartilage tissues from pre-arthritic and/or early arthritic hips. Over the past decade, there has been an increased utilization of hip joint preservation procedures designed to surgically “normalize” or improve the mechanical environment of pre-arthritic and early arthritic hips20,21. A common component of hip joint preservation procedures for femoroacetabular impingement is resection of a prominent anterolateral femoral head-neck junction to relieve mechanical impingement22-25. The articular cartilage harvested from this tissue provides unique biologic specimens for the analysis of metabolic activity and gene expression in articular chondrocytes. We quantified mRNA (messenger RNA) expression of genes that are potentially important in the development of secondary osteoarthritis in hips with femoroacetabular impingement. The first goal of this study was to quantify the expression of genes for inflammatory cytokines and chemokines (IL-1β, IL-8, CXCL1, CXCL2, CXCL3, CXCL6, CCL3, and CCL3L1), degradative enzymes (MMP-13 and ADAMTS-4), and major structural proteins in the cartilage extracellular matrix (COL2A1 and ACAN) (see Table I for definitions) in articular cartilage harvested from normal hips and hips with femoroacetabular impingement and end-stage osteoarthritis. The second goal was to analyze the relative expression of these genes in articular cartilage harvested at various stages of the osteoarthritic cascade.