Exogenous methods to control hypertrophy and collagen type X deposition include the re-
duction of calcium concentrations [134].TGF-β1/Smad3 signals inhibit hypertrophy [135], as well
as FGF-2, which has been shown to reduce hypertrophy when added to the culture medium [136].
As Rac1 and Cdc42 overexpression has been shown to accelerate hypertrophy, the pharmacological
inhibition of p38 signaling, which blocks the effects of Rac1 and Cdc42 overexpression, also re-
duces hypertrophy [132]. It has also been shown that blocking the α1β1-integrin prevents FXIIIA
from inducing chondrocyte hypertrophy [137]. OP-1 is another candidate whose inhibition lowers
the expression of collagen type X [138]. Parathyroid hormone-related protein has also been shown
to have inhibitory effects on collagen type X expression [139]. Lastly, overexpression of Smad6 in
chondrocytes results in delayed hypertrophy to the point of abolishing BMP-2’s expected effect of
hypertrophy induction [140]. Thyroxine’s prevention of Meckels cartilage from undergoing hyper-
trophy is also related to the topic at hand [141], though the cells in this case are derived from the
neural crest. Whereas tissue engineered cartilages formed from differentiated chondrocytes have sel-
dom been reported as undergoing calcification (except for select cases where chondrocytes from the
calcified zone were used [142], the expansion of the field into stem cells would require a fine control
and termination of cell differentiation. The methods listed above may be employed to prevent these
cells from progress to hypertrophy.
Cartilages from skeletally immature,mature,and older patients display several prominent differences.
While adult cartilage is avascular, immature cartilage can contain blood vessels as the cartilage is still
undergoing edochondral ossification. Because of this, immature cartilage also appears thicker than
mature cartilage, and cartilage continues to decrease in thickness as a person ages [143145]. The
cellularity, likewise, decreases with age [146]. Miotic cells can still be seen in immature cartilage.
With the development of a defined calcified zone and, later, closure of the epiphyseal plate, cartilage
division is seldom seen in healthy tissue. In addition to fewer chondrocytes, age also brings about
lowered metabolic activity, increased apoptosis, and subdued response to growth factors [147149],
characteristics that are antithetical to healing and to the facile use of older chondrocytes in tissue
Collagen crosslinking has been observed to increase with age [150]. Increased glycation (non-
enzymatic glycosylation, where sugars are added) of this matrix component also makes cartilage
stiffer, but more brittle and prone to failure [151]. Younger cartilage displays greater birefringence,
indicative of a greater degree of collagen alignment, as compared to older tissues [152]. Lastly,
collagen type XI fragments are only seen in young cartilage (below nineteen years of age), a possible
indication the collagen turnover slows down significantly beyond this point [153].
Significant changes are also seen with the proteoglycan content of cartilage with age. As the
tissue matures and ages, proteoglycan content decreases with concomitant reductions in the protein
core size, resulting in molecular weight decreases [154]. Chondroitin content decreases [155], and
link protein fragments with time [156], reducing the amount of aggrecan in the tissue. Despite these

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