Abstract
ABSTRACTDiabetic bone disease is a complication of type I and type II diabetes, both of which are increasing in the United States and elsewhere. Increased hip and foot fracture rates do not correlate well with changes in bone mineral density (BMD), whereas studies support the importance of collagen structure to bone strength. Extracellular lysyl oxidase (LOX) catalyzes the oxidative deamination of hydroxylysine and lysine residues in collagens resulting in aldehydes that subsequently form critically important biosynthetic crosslinks that stabilize functional collagens. Although LOX‐dependent biosynthetic crosslinks in bone collagen are deficient in diabetic bone, the expression and regulation of bone LOXs in diabetes have not been comprehensively studied. Here, we found that LOX is profoundly downregulated in bone in diabetes. Moreover, we have identified a novel metabolic regulatory relationship that is dysregulated in diabetes using mouse models. Data indicate that the incretin (gastric hormone) known as glucose‐dependent insulinotropic polypeptide (GIP) that is anabolic to osteoblasts strongly upregulates LOX, and that this regulation is disrupted in the streptozotocin‐induced model of diabetes in mice. In vivo and in vitro studies support that diabetes results in elevated circulating peripheral dopamine, likely also derived from the gut, and is responsible for blocking GIP signaling and LOX levels in osteoblasts. Moreover, peripheral administration of the dopamine D2 receptor antagonist amisulpride to diabetic mice restored trabecular bone structure to near normal and partially reversed downregulation of LOX. Taken together our data identifies a novel metabolic relationship between the gut‐derived hormone GIP and bone‐derived LOX, and points to the importance of LOX dysregulation in the pathology of diabetic bone disease. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
Highlights
The National Diabetes Statistics Report from the Centers for Disease Control and Prevention (CDC) in 2017 states that more than 100 million US adults are living with diabetes, and it was reported as the seventh leading cause of death in the United States in 2015 (National Diabetes Statistics Report 2017; https://www.cdc.gov/diabetes/pdfs/data/statistics/ national‐diabetes‐statistics‐report.pdf)
Previous studies have reported that in mouse models of diabetes, there is an abnormal arrangement of collagen fibrils that results in a significant reduction in bone material properties without affecting the mineral component of bone.[7,8] Results from these studies suggest that these collagen defects are caused by either accumulation of non‐enzymatic advanced glycation end products or the observed abnormally low levels of lysyl oxidase (LOX)‐mediated enzymatic crosslinks.[7,9]
The brain.[25]. Here we propose a model for diabetic bone disease in which abnormally increased circulating gut‐derived dopamine in diabetes results in poor bone structure by antagonizing the glucose‐dependent insulinotropic polypeptide (GIP) signaling in osteoblasts, leading to decreased LOX production and subsequent deficiencies in the organic matrix component of diabetic bone
Summary
The National Diabetes Statistics Report from the Centers for Disease Control and Prevention (CDC) in 2017 states that more than 100 million US adults are living with diabetes, and it was reported as the seventh leading cause of death in the United States in 2015 (National Diabetes Statistics Report 2017; https://www.cdc.gov/diabetes/pdfs/data/statistics/ national‐diabetes‐statistics‐report.pdf). Low BMD is used to diagnose osteopenia but often does not correlate well with the actual impairment in mechanical properties seen in diabetic bone in type I and type II diabetes.[6] Bone is a composite material consisting of both a mineral phase, composed of hydroxyapatite, and an organic phase that is mainly type I collagen. Previous studies have reported that in mouse models of diabetes, there is an abnormal arrangement of collagen fibrils that results in a significant reduction in bone material properties without affecting the mineral component of bone.[7,8] Results from these studies suggest that these collagen defects are caused by either accumulation of non‐enzymatic advanced glycation end products or the observed abnormally low levels of lysyl oxidase (LOX)‐mediated enzymatic crosslinks.[7,9]
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