Page 370 - Advances in Biomechanics and Tissue Regeneration

18.3 CARTILAGE REPAIR AND OSTEOARTHRITIS 367

Mammals accumulate senescent cells as they age, contributing to aging per se and age-related disease [26]. In artic-
ular cartilage, senescence may predispose joint tissues to osteoarthritis development and/or progression; senescent
cells have been observed near osteoarthritic lesions but not in intact cartilage from the same patient [26, 27].
Cellular senescence is mediated via signal transduction; cells enter stable growth arrest but remain metabolically
active. However, senescent cell persistence and accumulation impair cartilage function [26]. Aging chondrocytes
exhibit signs of senescence, losing the ability to divide, which is the major factor contributing to deterioration of car-
tilage homeostasis and function [9, 28]. Senescence is associated with diminished mitotic activity and telomere short-
ening [25, 29], but other factors that do not affect telomere length are also in play; Martin et al. [29] showed that in vitro
exposure to mechanical loading increased chondrocyte oxidative stress that ultimately caused senescence without any
reduction in telomere length.
Therefore, increasing age triggers decline in chondrocyte function caused by senescence and, hence, diminished
remodeling and maintenance capacities. The lack of tissue turnover and renewal triggers end-product accumulation,
increasing stiffness caused by fibrillar cross-linking, followed by declines in articular cartilage quality and deformation
capacity and, ultimately an increased susceptibility to destruction. Thus age is a major predisposing factor for the
development of osteoarthritis [23].
The cell density of articular cartilage decreases with age, because apoptosis increases [30, 31]. Moreover, articular
chondrocytes exhibit reduced proteoglycan synthesis and altered proteoglycan composition, modifying the biome-
chanical properties of the ECM [14]. Thus the articular cartilage of elderly individuals exhibits a diminished capacity
for deformation in vivo compared with that of younger individuals [32]. Also, senescent cells act synergistically with
inflammation to drive further cellular senescence [26].
Structural changes in collagen fibers also develop with age, contributing to weakening of fibrillar elasticity and,
therefore, of biomechanical properties: type II collagen fibers become larger in diameter, increasing stiffness and
decreasing the resistance of articular cartilage to tension, mainly because of fibrillar cross-linking with advanced gly-
cation end products [14, 33]. With increasing age, type II collagen synthesis decreases, the expression and activity of
MMPs and several collagenases increase, and increased proteolytic fragmentation of collagen molecules is apparent,
promoting matrix remodeling and reducing tensile strength, in turn causing articular fibrillation and erosion [34, 35].
These changes commence via disruption of the superficial zone of articular cartilage, progressing later to deeper zones
in the degenerative disease termed osteoarthritis.
Holmes et al. [36] showed that the total amount of aggrecan did not change with age; however, these results are
controversial since the sizes of large proteoglycan aggregates decreased with age [14], accompanied by shortening
of keratan sulfate and chondroitin sulfate chains, as well as the size of HA. In contrast, the proportion of HA in
the ECM increased fourfold from birth to 90years of age [34]. Aggrecanase proteolytic activity increased with age;
aggrecan fragments were released into synovial fluid, leaving HA binding domains free for occupation by other mol-
ecules, thus limiting formation of fully functional aggregates [37]. Therefore, proteoglycan synthesis and level fall with
age [13], reducing the ECM intercellular water content, finally altering the biomechanical properties of articular car-
tilage in a manner compromising function.
In addition, age-related changes in subchondral bone, which often undergoes significant remodeling [38], probably
affect joint oxygen tensions, as does increased cartilage calcification, associated with advancing age [9].

18.3 CARTILAGE REPAIR AND OSTEOARTHRITIS

Cartilage changes and loss of cartilage thickness in synovial joints with aging contribute to the development of oste-
oarthritis, the most common disease of synovial joints, causing progressive reduction of mobility and increased pain
on joint movement [16]. Several risk factors are associated with the development of osteoarthritis: gender (females are
at higher risk), genetic predisposition, obesity, and advancing age [14, 39, 40]. Small injuries can trigger osteoarthritis in
younger subjects because, although articular cartilage can tolerate intense repetitive stress, cartilage manifests a strik-
ing inability to heal even after very minor injury, given its avascularity, chondrocyte immobility, and the limited ability
of mature chondrocytes to proliferate [1].
Osteoarthritis features various changes in synovial joint components, including progressive degeneration of artic-
ular cartilage, formation of bony peripheral outgrowths (osteophytes), changes in subchondral bone, thickening of
both the synovium and ligaments, and (in many cases) synovial inflammation (synovitis) [26].
Moderate loading exerts a beneficial effect on osteoarthritis, associated with cartilage hypertrophy and maintenance
of articular cartilage quality via increases in lubricin levels, regardless of age [23]. However, joint overloading (as in
overweight subjects) affects cartilage composition; depending on loading intensity, the earliest damage is softening

II. MECHANOBIOLOGY AND TISSUE REGENERATION