distortion, and proliferation continues. Collagens type II, IX, and XI are rendered more soluble by
the catabolic activity. The breakup of the collagen network results in TGF-β being released from
the matrix, and greater collagen type VI production and sequestration by the cells ensue. Finally,
many cells, encapsulated by a sheath of collagen type VI, now occupy a distorted chondron, where
one or two cells used to reside [267].
Cartilage has long been considered immune-privileged because it is avascular and alymphatic.
The dense, hyaline matrix greatly hinders cell movement and, as discussed earlier, is a barrier to even
chondrocytes themselves, precluding a complete healing response as the sequestered chondrocytes
are prevented from populating the wound edge. This same dense matrix also serves as a barrier to
integration, which will be discussed in the last section of this book, in Section 5.2.2. For the time
being,it is important to note that, unless compromised,this dense tissue locks cells and matrix in,and
keeps cells out. How, then, does inflammation wreak such havoc on this tissue? As the disease pro-
gresses the thickening and increasingly hypervascular synovium secretes matrix metalloproteinases
(MMPs) and aggrecanases. In addition, chondrocyte death can be observed much earlier than matrix
degradation, and as a result, releases secondary necrosis factors that diffuse to initiate apoptosis in
neighboring cells. In this case, the dense matrix becomes a space that the chondrocytes cannot escape
from, and the chondron a place where phagocytes cannot reach to clear apoptotic debris to interrupt
the cycle of inflammation and necrosis [268].
Other molecular factors that appear to serve as players in OA progression include F-spondin,a
neuronal extracellular matrix glycoprotein. Approximately a 7-fold increase for this species is seen in
OA cartilage, and its presence primes TGF-β1 and prostaglandin E2 (PGE2) release [269]. PGE2
is a proinflammatory mediator, and its release is also accompanied by collagen degradation and
MMP-13 activation when cartilage explants are stimulated with F-spondin.The increased synthesis
of COMP by chondrocytes and synoviocytes has also been associated with OA, as its production
can be stimulated by TGF-β1[270].
OA causes significant pain and suffering to individual patients, and the economic burden of this
disease for society is great [271]. For example,in the US alone OA related costs exceed $65 billion per
year (both medical costs and lost wages) [218]. Conservatively, it is estimated that 1 in 8 American
adults over the age of 25 have clinically manifested OA [220, 272], making it one of the leading
causes of disability in the United States [225]. Increased cost associated with OA and rheumatoid
arthritis (RA) are high as it has been demonstrated that several other comorbid conditions exist,
such as anemia, osteoporosis, and bacterial infection [228]. Analyses show that, when compared to
patients without OA and RA,significantly more charges are incurred by OA and RA patients in other
areas such as respiratory,cardiovascular,gastrointestinal,neurological, and psychiatric conditions, and
also for general medical care. Increased therapeutic procedures, physician services, use of prescription
medication, etc., are also more prevalent in sufferers of OA and RA [273]. Another significant source
of costs is loss of productivity. Indirect costs associated with articular cartilage injuries (that have

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