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Abstract
Bone collagen cross-links are now widely used to assess bone resorption levels in
many metabolic bone diseases. The post-translational modifications of bone and other
mineralizing collagens are significantly different from those of other type I collagen
matrices, a fact that has been exploited during recent advances in the development
of biochemical markers of bone resorption. The enzymatic collagen cross-linking mechanism
is based upon aldehyde formation from specific telopeptide lysine or hydroxylysine
residues. The immature ketoimine cross-links in bone form via the condensation of
a telopeptide aldehyde with a helical lysine or hydroxylysine. Subsequent maturation
to the pyridinoline and pyrrole cross-links occur by further reaction of the ketoimines
with telopeptide aldehydes. In mineralizing tissues, a relatively low level of lysyl
hydroxylation results in low levels of hydroxylysyl pyridinoline, and the occurrence
of the largely bone specific lysyl pyridinoline and pyrrolic cross-links. The collagen
post-translational modifications appear to play an integral role in matrix mineralization.
The matrix of the turkey tendon only mineralizes after a remodeling of the collagen
and the subsequent formation of a modified matrix more typical of bone than tendon.
Further, disturbances in the post-translational modification of collagen can also
affect the mineralization density and crystal structure of the tissue. In addition
to their use as a convenient measure of matrix degradation, collagen cross-links are
of significant importance for the biomechanical integrity of bone. Recent studies
of osteoporotic bone, for example, have demonstrated that subtle perturbations in
the pattern of lysine hydroxylation result in changes in the cross-link profile. These
alterations, specifically changes in the level of the pyrrolic cross-link, also correlate
with the strength of the bone. Further research into the biochemistry of bone collagen
cross-links may expand current understanding and their clinical application in metabolic
bone disease. This review also demonstrates the potential for further study into this
area to provide more subtle information into the mechanisms and etiology of disease
and aging of mineralizing tissues.