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: Anil Bhatta, Rajnikumar Sangani, Ravindra Kolhe, Haroldo A Toque, Michael Cain, Abby Wong, Nicole Howie, Rahul Shinde, Mohammed Elsalanty, Lin Yao, Norman Chutkan, Monty Hunter, Ruth B Caldwell, Carlos Isales, R William Caldwell, Sadanand Fulzele
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 422 Pg. 211-220 (Feb 15 2016) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 26704078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Published by Elsevier Ireland Ltd.

Chemical References

• Nitric Oxide
• Sucrose
• Streptozocin
• Arginine
• Arg1 protein, mouse
• Arginase
• Glucose

Topics

• Animals
• Arginase (metabolism)
• Arginine (metabolism)
• Bone Density
• Bone and Bones (cytology, enzymology, pathology)
• Cells, Cultured
• Diabetes Mellitus, Experimental (chemically induced, enzymology, pathology)
• Diet, High-Fat (adverse effects)
• Glucose (pharmacology)
• Mesenchymal Stem Cells (drug effects, enzymology)
• Mice
• Nitric Oxide (metabolism)
• Streptozocin
• Sucrose (adverse effects)
• Up-Regulation