The role of structural genes in the pathogenesis of osteoarthritic disorders

Arthritis Research & Therapy, Aug 2002

Osteoarthritis (OA), one of the most common age-related chronic disorders of articular cartilage, joints, and bone tissue, represents a major public health problem. Genetic studies have identified multiple gene variations associated with an increased risk of OA. These findings suggest that there is a large genetic component to OA and that the disorder belongs in the multigenetic, multifactorial class of genetic diseases. Studies of chondrodysplasias and associated hereditary OA have provided a better understanding of the role of structural genes in the maintenance and repair of articular cartilage, in the regulation of chondrocyte proliferation and gene expression, and in the pathogenesis of OA.

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The role of structural genes in the pathogenesis of osteoarthritic disorders

Arthritis Research 1465-9905 The role of structural genes in the pathogenesis of osteoarthritic disorders Anthony M Reginato1,2 and Bjorn R Olsen1 0 Department of Rheumatology, Allergy and Immunology, Massachusetts General Hospital , Boston, MA USA 1 Department of Cell Biology, Harvard Medical School , Boston, MA , USA Osteoarthritis (OA), one of the most common age-related chronic disorders of articular cartilage, joints, and bone tissue, represents a major public health problem. Genetic studies have identified multiple gene variations associated with an increased risk of OA. These findings suggest that there is a large genetic component to OA and that the disorder belongs in the multigenetic, multifactorial class of genetic diseases. Studies of chondrodysplasias and associated hereditary OA have provided a better understanding of the role of structural genes in the maintenance and repair of articular cartilage, in the regulation of chondrocyte proliferation and gene expression, and in the pathogenesis of OA. cartilage; chromosomes; genetics; linkage; osteoarthritis Introduction Osteoarthritis (OA), the most common form of arthritis, is no longer regarded as a simple consequence of agerelated cartilage degeneration, but rather is regarded as the result of an active process, which may be regenerative rather than degenerative in nature. Furthermore, OA is probably not a single disorder, but rather a group of overlapping distinct diseases. These diseases are the consequences of mechanical or biological events that destabilize the normal coupling of synthesis and degradation of extracellular matrix in articular cartilage and subchondral bone. It is commonly assumed that multiple factors, including genetic and developmental, metabolic, and traumatic factors can trigger osteoarthritic disease. At later stages, the disease is characterized by molecular, morphological, and biomechanical changes which lead to softening, fibrillation, ulceration, and loss of articular cartilage, eburnation of subchondral bone, osteophytes, and subchondral bone cysts [ 1 ]. Extracellular matrix molecules play a critical role in the normal maintenance of articular cartilage structure, regulation of chondrocyte proliferation and gene expression, and cartilage aging and repair, and they are important in the pathophysiology of OA. Articular cartilage is composed of an extracellular matrix designed to resist tensile and compressive forces and provide a smooth surface to permit low-friction movement in joints. These properties are the result of the interactions between a large number of proteins and proteoglycans present in the matrix (Fig. 1). Many of these components are listed in Table 1; this list, which is by no means exhaustive, includes those components that have been studied the most. Type II collagen is the major collagenous component, but collagens III, VI, IX, X, XI, XII, and XIV also contribute to the mature cartilage matrix. Noncollagenous components include large amounts of the hyaluronate-binding proteoglycan aggrecan and its associated link protein, as well as other collagen-binding proteoglycans, such as decorin, fibromodulin, and lumican, and proteins such as PRELP (proline/arginine-rich and leucine-rich repeat protein) and cartilage oligomeric matrix protein (COMP) [ 2 ]. The structure and abundance of these components change with age because of a combination of changes in both synthetic and degradative events [ 3 ]. The effects of mutations in the genes encoding these structural components of the matrix have provided insight into the function of the individual gene products in the pathogenesis of OA. ANKH = human homologue of the mouse progressive ankylosis (ank) gene; COMP = cartilage oligomeric matrix protein; CMP = cartilage matrix protein; IL-1 = interleukin-1; MED = multiple epiphyseal dysplasia; OA = osteoarthritis; PGOA = primary generalized osteoarthritis; SED = spondyloepiphyseal dysplasia; TGFβ1 = transforming growth factor beta 1. Diagram showing the collagen components (collagens II, IX and XI) of cartilage fibril (top) and the association between the fibril and noncollagenous components of cartilage, such as matrilin-3, COMP, and complexes of aggrecan, link protein and hyaluronan (bottom). COMP, cartilage oligomeric matrix protein. Large genetic component in osteoarthritis Twin studies and cohort studies have highlighted a surprisingly large genetic component to OA [ 4–6 ]. These findings have prompted the search for predisposing genes using parametric linkage analyses of rare families in which OA segregates as a Mendelian trait, model-free linkage analysis of affected sibling pairs, and association analysis of known candidate genes. Linkage studies have highlighted chromosomes 1, 2, 4, 6, 7, 9,11-13,16,19, and X as potential chromosomes with OA susceptibility genes [ 7–15 ]. Chromosomes 2,4,7,11, and 16 have been identified in multiple genome-wide scans and are therefore the most likely (...truncated)


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Anthony M Reginato, Bjorn R Olsen. The role of structural genes in the pathogenesis of osteoarthritic disorders, Arthritis Research & Therapy, 2002, pp. 337-345, 4, DOI: 10.1186/ar595