AGE-RELATED INCREASE IN KYNURENINE LINKED TO DECREASED OSTEOGENESIS VIA REDUCED SDF-1 IN MESENCHYMAL STEM CELLS. (11th November 2018)

• Record Type: Journal Article
• Authors: Hussein, K; Elmansi, A; Volkman, B; Shi, X; McGee-Lawrence, M; Hamrick, M; Isales, C; Hill, W
• Is Part Of: Innovation in aging. Volume 2(2018)Supplement 1
• Page Start: 96
• Page End: 96
• Publication Date: 2018-11-11
• Subjects: Aging -- Periodicals; Gerontology -- Periodicals; 612.67
• DOI: 10.1093/geroni/igy023.362
• Languages: English
• ISSNs: 2399-5300

Abstract

Abstract: Stromal cell-derived factor-1 (SDF-1α /CXCL12) is a member of the pro-inflammatory CXC chemokine family. Our group previously reported the role of SDF-1α in in-vitro osteogenic differentiation and in vivo bone formation. In addition, SDF-1α is an essential factor for migration and homing of bone marrow-derived mesenchymal stem cells (BMSCs). Recently, high levels of kynurenine (KYN), a Tryptophan (Trp) metabolite generated by Indoleamine-(2, 3)-dioxygenase (IDO1), have been linked to many age-associated diseases including reduced bone mass. We hypothesized that KYN acts on bone loss by attenuating BMSC SDF-1α levels via the KYN receptor aryl hydrocarbon receptor (Ahr). In vitro, serial doses of KYN (25, 50, 100, 200 µM) were used to treat BMSCs, in both normoxic and acute hypoxic (3% O2) conditions. Levels of SDF-1α gene and protein expression were evaluated in supernatant of these cells using qRT-PCR and ELISA at 24 and 48 hours. IDO1 levels were evaluated at 30 mins and 48 hours, respectively. Our results show that KYN, induced a significant dose dependent decrease in SDF-1α gene and the protein expression out through 48 hours, while inhibition of AhR with CH223191 partially reversed the decrease in SDF-1. In turn, increasing SDF-1 levels can significantly reduce both AhR and IDO1 gene expression. Additionally, KYN significantly decreased the genetic expression levels of the SDF-1 receptors CXCR4 and CXCR7. These results suggest that elevated levels of KYN might contribute to age related bone loss by attenuating levels of SDF-1α in BMSCs via an AhR transcription factor dependent pathway.