Modifications of Collagen Cause Age-Related Decline in Structural Function of the Extracellular Matrix

In the paper linked here, researchers catalog some of the harm done by age-related modifications to the collagen molecules of the extracellular matrix, with particular attention given to bone. The extracellular matrix is constructed by cells, and its intricate molecular structure, largely consisting of forms of collagen, determines the properties of that tissue: elasticity in skin, for example, or ability to bear load in bone. Chemical modifications to collagen molecules, especially cross-linking by advanced glycation end-products in which different molecules are chained together, disrupt the physical and structural properties of the matrix. This is one of the causes of age-related loss of elasticity in skin and blood vessels, for example, the second of which is ultimately fatal. In principle all of these causes can be reversed and addressed: chemical bonds can be broken, cross-links attacked and disassembled with designed drugs. This is still a work in progress, however, in need of greater support and funding.

During aging, changes occur in the collagen network that contribute to various pathological phenotypes in the skeletal, vascular, and pulmonary systems. The aim of this study was to investigate the consequences of age-related modifications on the mechanical stability and in vitro proteolytic degradation of type I collagen. Analyzing mouse tail and bovine bone collagen, we found that collagen at both fibril and fiber levels varies in rigidity and Young's modulus due to different physiological changes, which correlate with changes in cathepsin K (CatK)-mediated degradation.

A decreased susceptibility to CatK-mediated hydrolysis of fibrillar collagen was observed following mineralization and advanced glycation end product-associated modification. However, aging of bone increased CatK-mediated osteoclastic resorption by ∼27%, and negligible resorption was observed when osteoclasts were cultured on mineral-deficient bone. We observed significant differences in the excavations generated by osteoclasts and C-terminal telopeptide release during bone resorption under distinct conditions. Our data indicate that modification of collagen compromises its biomechanical integrity and affects CatK-mediated degradation both in bone and tissue, thus contributing to our understanding of extracellular matrix aging.

Link: http://dx.doi.org/10.1074/jbc.M115.644310

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