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)