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Kynurenine, a Tryptophan Metabolite That Accumulates With Age, Induces Bone Loss.


ABSTRACT: Age-dependent bone loss occurs in humans and in several animal species, including rodents. The underlying causal mechanisms are probably multifactorial, although an age-associated increase in the generation of reactive oxygen species has been frequently implicated. We previously reported that aromatic amino acids function as antioxidants, are anabolic for bone, and that they may potentially play a protective role in an aging environment. We hypothesized that upon oxidation the aromatic amino acids would not only lose their anabolic effects but also potentially become a catabolic byproduct. When measured in vivo in C57BL/6 mice, the tryptophan oxidation product and kynurenine precursor, N-formylkynurenine (NFK), was found to increase with age. We tested the direct effects of feeding kynurenine (kyn) on bone mass and also tested the short-term effects of intraperitoneal kyn injection on bone turnover in CD-1 mice. ?CT analyses showed kyn-induced bone loss. Levels of serum markers of osteoclastic activity (pyridinoline [PYD] and RANKL) increased significantly with kyn treatment. In addition, histological and histomorphometric studies showed an increase in osteoclastic activity in the kyn-treated groups in both dietary and injection-based studies. Further, kyn treatment significantly increased bone marrow adiposity, and BMSCs isolated from the kyn-injected mice exhibited decreased mRNA expression of Hdac3 and its cofactor NCoR1 and increased expression of lipid storage genes Cidec and Plin1. A similar pattern of gene expression is observed with aging. In summary, our data show that increasing kyn levels results in accelerated skeletal aging by impairing osteoblastic differentiation and increasing osteoclastic resorption. These data would suggest that kyn could play a role in age-induced bone loss. © 2017 American Society for Bone and Mineral Research.

SUBMITTER: Refaey ME 

PROVIDER: S-EPMC5685888 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Kynurenine, a Tryptophan Metabolite That Accumulates With Age, Induces Bone Loss.

Refaey Mona El ME   McGee-Lawrence Meghan E ME   Fulzele Sadanand S   Kennedy Eileen J EJ   Bollag Wendy B WB   Elsalanty Mohammed M   Zhong Qing Q   Ding Ke-Hong KH   Bendzunas Nathaniel G NG   Shi Xing-Ming XM   Xu Jianrui J   Hill William D WD   Johnson Maribeth H MH   Hunter Monte M   Pierce Jessica L JL   Yu Kanglun K   Hamrick Mark W MW   Isales Carlos M CM  

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20170814 11


Age-dependent bone loss occurs in humans and in several animal species, including rodents. The underlying causal mechanisms are probably multifactorial, although an age-associated increase in the generation of reactive oxygen species has been frequently implicated. We previously reported that aromatic amino acids function as antioxidants, are anabolic for bone, and that they may potentially play a protective role in an aging environment. We hypothesized that upon oxidation the aromatic amino aci  ...[more]

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