Citrullination of the matrix: a potential link to age related changes in bone tissue
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There is a strong correlation between aging and risk of fractures that is independent of changes in bone quantity. Although the underlying processes that dysregulate the structural health and integrity of bone tissue without affecting bone-quantity with aging are unknown, one hypothesis is that changes affecting extra-cellular components of bone, particularly components of the mineralized matrix, may contribute to the decline in bone quality with aging. Citrullination is a post-translational modification where a peptidyl arginine is enzymatically modified to a peptidyl Citrulline by enzymes knowns as peptidyl arginine deiminases (PADs). Increased citrullination of proteins is associated with altered protein function and a loss of structural stability. We propose that citrullination could have negative effects on the structural integrity of bone matrix proteins by inducing a loss of proteostasis, a conditional loss of protein homeostasis. To address this, we examined whether the levels of citrullinated bone matrix proteins differs between young and old mice. Our results show that there is a profound increase in citrullination of extractable bone matrix with ageing. To assess if changes in citrullination contribute to bone mass and/or mechanical strength, we utilized an existing murine model in which citrullination is increased. Mice deficient in Protein Tyrosine Phosphatase Nonreceptor 22 (PTPN22), an inhibitor of PAD4, and thus of citrullination, have been shown to have increased histone H3 citrullination in macrophages derived from Ptpn22-/- mice compared to WT controls. We assessed several properties of bone in both young and aged Ptpn22-/- animals. In young mice, deficiency in PTPN22 leads to an increase in bone matrix citrullination. However, we did not find a link between increased citrullination and bone loss, as measured by formation of bone resorbing osteoclasts. Further, no difference in bone mass or structural parameters was seen in either young or old Ptpn22-/- mice compared to wild-type littermates. Interestingly, there was also no clear relationship between degree of citrullinated bone matrix and genotype in older mice, possibly due to overall increases in bone matrix citrullination with aging. However, as it is clear that bone matrix citrullination increases with age and that this citrullination in younger mice can be modulated by PTPN22 deficiency, we plan to use Ptpn22-/- mice as a model to learn more about the effects of increased citrullination on mechanical strength and bone matrix properties, therefore unearthing new insights into the role of post-translational modification in the function of bone matrix proteins.