title: Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model.
abstract: A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of l-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of l-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Bhatta
authors.affiliation: Departments of Orthopaedic Surgery, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Rajnikumar
authors.initials: R
authors.lastname: Sangani
authors.affiliation: Departments of Pathology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kolhe
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Haroldo A
authors.initials: HA
authors.lastname: Toque
authors.affiliation: Departments of Orthopaedic Surgery, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cain
authors.affiliation: Departments of Orthopaedic Surgery, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Wong
authors.affiliation: School of Dentistry, Georgia Regents University, Augusta, GA 30912, Augusta, GA 30912, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Howie
authors.affiliation: Departments of Pathology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Shinde
authors.affiliation: School of Dentistry, Georgia Regents University, Augusta, GA 30912, Augusta, GA 30912, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Elsalanty
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yao
authors.affiliation: The CORE Institute, Phoenix, AZ 85023, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Chutkan
authors.affiliation: Departments of Orthopaedic Surgery, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Monty
authors.initials: M
authors.lastname: Hunter
authors.affiliation: Cell Biology and Anatomy and Vascular Biology Center, Georgia Regents University; Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.affiliation: Departments of Orthopaedic Surgery, Georgia Regents University, Augusta, GA 30912, USA; Institute of Regenerative and Reparative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Isales
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: wcaldwel@gru.edu.
authors.forename: R William
authors.initials: RW
authors.lastname: Caldwell
authors.affiliation: Departments of Orthopaedic Surgery, Georgia Regents University, Augusta, GA 30912, USA; Institute of Regenerative and Reparative Medicine, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: sfulzele@gru.edu.
authors.forename: Sadanand
authors.initials: S
authors.lastname: Fulzele
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D015519:Bone Density; D001842:Bone and Bones / Q000166:cytology / Q000201:enzymology / Q000473:pathology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005947:Glucose / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D013311:Streptozocin; D013395:Sucrose / Q000009:adverse effects*; D015854:Up-Regulation
chemical_list: D009569:Nitric Oxide; D013395:Sucrose; D013311:Streptozocin; D001120:Arginine; C544448:Arg1 protein, mouse; D001119:Arginase; D005947:Glucose
keywords: Arginase; Bone complications; Diabetic mouse model; High-fat/high-sucrose diet