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

Mona El Refaey, Meghan Elizabeth McGee Lawrence, Sadanand T Fulzele, Eileen J. Kennedy, Wendy B Bollag, Mohammed Elsayed Elsalanty, Qing Zhong, Kehong Ding, Nathaniel G. Bendzunas, Xing Ming Shi, Jianrui Xu, William D Hill, Maribeth H Johnson, David M Hunter, Jessica L. Pierce, Kanglun Yu, Mark W Hamrick, Carlos M Isales

Research output: Contribution to journalArticle

17 Citations (Scopus)

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. μCT 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.

Original languageEnglish (US)
Pages (from-to)2182-2193
Number of pages12
JournalJournal of Bone and Mineral Research
Volume32
Issue number11
DOIs
StatePublished - Nov 1 2017

Fingerprint

Kynurenine
Tryptophan
Bone and Bones
Aromatic Amino Acids
Anabolic Agents
Bone Remodeling
Adiposity
Intraperitoneal Injections
Inbred C57BL Mouse
Rodentia
Reactive Oxygen Species
Antioxidants
Biomarkers
Bone Marrow

Keywords

  • AGING
  • BONE LOSS
  • INDOLEAMINE 2,3 DIOXYGENASE
  • KYNURENINE

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Kynurenine, a Tryptophan Metabolite That Accumulates With Age, Induces Bone Loss. / Refaey, Mona El; McGee Lawrence, Meghan Elizabeth; Fulzele, Sadanand T; Kennedy, Eileen J.; Bollag, Wendy B; Elsalanty, Mohammed Elsayed; Zhong, Qing; Ding, Kehong; Bendzunas, Nathaniel G.; Shi, Xing Ming; Xu, Jianrui; Hill, William D; Johnson, Maribeth H; Hunter, David M; Pierce, Jessica L.; Yu, Kanglun; Hamrick, Mark W; Isales, Carlos M.

In: Journal of Bone and Mineral Research, Vol. 32, No. 11, 01.11.2017, p. 2182-2193.

Research output: Contribution to journalArticle

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AU - McGee Lawrence, Meghan Elizabeth

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AU - Bollag, Wendy B

AU - Elsalanty, Mohammed Elsayed

AU - Zhong, Qing

AU - Ding, Kehong

AU - Bendzunas, Nathaniel G.

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AU - Xu, Jianrui

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