Age-related increase of kynurenine enhances miR29b-1-5p to decrease both CXCL12 signaling and the epigenetic enzyme Hdac3 in bone marrow stromal cells
Ahmed M. Elmansi,
Khaled A. Hussein,
Sergio Mas Herrero,
Sudharsan Periyasamy-Thandavan,
Alexandra Aguilar-Pérez,
Galina Kondrikova,
Dmitry Kondrikov,
Nada H. Eisa,
Jessica L. Pierce,
Helen Kaiser,
Ke-Hong Ding,
Aisha L. Walker,
Xue Jiang,
Wendy B. Bollag,
Mohammed Elsalanty,
Qing Zhong,
Xing-ming Shi,
Yun Su,
Maribeth Johnson,
Monte Hunter,
Charles Reitman,
Brian F. Volkman,
Mark W. Hamrick,
Carlos M. Isales,
Sadanand Fulzele,
Meghan E. McGee-Lawrence,
William D. Hill
Affiliations
Ahmed M. Elmansi
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States of America
Khaled A. Hussein
Department of Oral Surgery and Medicine, National Research Centre, Cairo, Egypt
Sergio Mas Herrero
Dept. of Psychiatry, Universitat de Barcelona, Spain
Sudharsan Periyasamy-Thandavan
Georgia Cancer Center, Augusta University, Augusta, GA 30912, United States of America
Alexandra Aguilar-Pérez
Department of Anatomy and Cell Biology, Indiana University School of Medicine in Indianapolis, IN, United States of America; Department of Cellular and Molecular Biology, School of Medicine, Universidad Central del Caribe, Bayamon 00956, Puerto Rico; Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Galina Kondrikova
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States of America
Dmitry Kondrikov
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States of America
Nada H. Eisa
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States of America; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Jessica L. Pierce
Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Helen Kaiser
Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Ke-Hong Ding
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Aisha L. Walker
Department of Medicine, Vascular Medicine Institute, University of Pittsburg School of Medicine, Pittsburg, PA 15261, United States of America
Xue Jiang
Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
Wendy B. Bollag
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Aueusta University, Augusta, GA 30912, United States of America; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States of America; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30904, United States of America; Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Mohammed Elsalanty
Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Qing Zhong
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Xing-ming Shi
Department of Orthopaedic Surgery, Medical College of Georgia, Aueusta University, Augusta, GA 30912, United States of America; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Yun Su
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Maribeth Johnson
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America; Department of Population Health Science, Augusta University, Augusta, GA 30912, United States of America
Monte Hunter
Department of Orthopaedic Surgery, Medical College of Georgia, Aueusta University, Augusta, GA 30912, United States of America
Charles Reitman
Orthopaedics and Physical Medicine Department, Medical University of South Carolina, Charleston, SC 29403, United States of America
Brian F. Volkman
Biochemistry Department, Medical College of Wisconsin, Milwaukee, WI 53226, United States of America
Mark W. Hamrick
Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Aueusta University, Augusta, GA 30912, United States of America; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States of America
Carlos M. Isales
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Aueusta University, Augusta, GA 30912, United States of America; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States of America; Division of Endocrinology, Diabetes and Metabolism, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America
Sadanand Fulzele
Department of Orthopaedic Surgery, Medical College of Georgia, Aueusta University, Augusta, GA 30912, United States of America; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States of America
Meghan E. McGee-Lawrence
Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Aueusta University, Augusta, GA 30912, United States of America; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States of America; Correspondence to: M.E. McGee-Lawrence, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, 1460 Laney Walker Blvd., CB1101, Augusta, GA 30912, United States of America.
William D. Hill
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29403, United States of America; Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States of America; Center for Healthy Aging, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States of America; Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30904, United States of America; Correspondence to: W.D. Hill, Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Thurmond/Gazes Bldg-Room 506A, 30 Courtenay Drive, Charleston, SC 29403, United States of America.
Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging.We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p.Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3′,4′-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis.