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collagen cross-links in the fractures, and without alteration in the levels
of collagen, AGE cross-links were found to be increased compared with age-
matched healthy subjects (343-345). Increase in the amount of cross-links
and hydroxylation of Lys residues in osteoporosis was shown to be induced
by a higher turnover of the bone (346). Increase in Lys modification is induced
by the overexpression of lysyl hydroxylase-2b in MC3T3-E1 osteoblasts and
caused the formation of thinner collagen fibrils, which resulted in defective
matrix mineralization, inducing bone fragility in osteoporosis (347). Pentosi-
dine as a cross-linking type of AGE was known to accumulate with increas-
ing age in bone (348, 349). However, the pentosidine content was found to be
high in both cortical and cancellous bone from patients with osteoporotic
femoral neck fractures when compared with age-matched healthy subjects.
Furthermore, it was high in even younger osteons, suggesting AGE cross-
link formation in newly formed collagen (344). High plasma homocysteine
(Hcy) levels as a reason for oxidative stress may be a fracture risk independent
from BMD (350). In a case control study, a decline in the actual amount of
enzymatic cross-links and a marked increase in pentosidine were observed in
bone from patients with postmenopausal osteoporotic hip fractures and mod-
erately elevated plasma Hcy (343). Blouin et al. demonstrated that the colla-
gen cross-link ratio was significantly higher in hip fracture cases with
hyperhomocysteinemia than in cases with normal Hcy plasma levels (351).
Herrmann et al. (352) demonstrated using a hyperhomocysteinemia-induced
rat model that Hcy seemed to accumulate specifically and bind to collagen in
bone, and the adverse effects of hyperhomocysteinemia on collagen cross-link
formation may predominate in bone collagen.
After collagen, osteocalcin is the second most abundant protein in the bone
matrix. Osteocalcin is a product of osteoblasts and contains the calcium-
binding amino acid
-carboxyglutamate. This amino acid helps osteocalcin for
binding to the principal mineral phase of bone hydroxyapatite. Osteocalcin is
mainly adsorbed to bone, but a small amount can be found in the circulation.
Osteocalcin in human bone might be post-translationally modified and has
been found to be glycated. In a study, 47 patients without diabetes from dif-
ferent ages were tested for the glycation of osteocalcin and levels of glycation
were found to be low in children, constant through adultness, and high in
individuals aged 60-97. The site of glycation was found to be the amino-
terminal tyrosine (353).
Carcinogenesis is associated with a wide range of factors. The process of trans-
formation from normal cells into cancer cells changes the cellular metabolism
and genetics and is directly linked to the progression of cancer. For hormone-
sensitive tissues (breast and endometrium), the development of cancer is
associated with oxygen-dependent modifications and excessive exposure to
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