Osteoblast Dopamine Receptor Mediates Diabetic Bone Disease

Abstract Diabetes is estimated to affect at least 100 million people in the United States. Diabetic bone disease is a complication of both type 1 and type 2 diabetes. Diabetic bone disease results in decreased mobility due to increased fracture risk with further complications that can ultimately be fatal. Low bone mineral density that is

often used to diagnose diabetic bone disease does not correlate well with the actual impairment in mechanical properties observed in type 1 and type 2 diabetes. By contrast, collagen in diabetic bone is well understood to have low levels of lysine-derived biosynthetic cross-links which are essential for the physical strength of

connective tissues, including bone. However, few studies of levels and regulation of lysyl oxidase in diabetic bone exist. Recent interest in gut-derived endocrine factors has developed from consequences of bariatric surgery to treat obese individuals, many of whom also suffer from diabetes. Glucose insulinotropic polypeptide

(GIP) is a gut-derived hormone known as an incretin. In addition to targeting pancreatic β cells, GIP directly target osteoblasts via the GIP receptor (GIPR), stimulating a bone anabolic response. The gut also secretes dopamine into the peripheral circulation that has been hypothesized to inhibit the activity of GIP, mediated by

dopamine receptors, also present on osteoblasts. Here we integrate these findings and our own data into the following paradigm-shifting proposal. Our hypothesis is that normal anabolic stimulation of bone formation and lysyl oxidase production by GIP is dysregulated in diabetes by gut-derived dopamine mediated by

the osteoblast dopamine D2 receptor (D2R) in both type 1 and type 2 diabetes. We propose to test this hypothesis in male and female C57BL6/J conditional osteoblast-specific D2r gene knockout mice (Col1-2.3-cre cross-bred with D2rfl/fl mice). Mice will be subjected to development of both type 1 and type 2 diabetes by,

respectively, multiple low dose streptozotocin injections (type 1 diabetes), and to high fat diet (type 2 diabetes). Analyses will include measures of bone markers by qPCR plus all five lysyl oxidase family mRNAs, bone structure by µCT, bone strength, bone histology for growth plate structure, and a variety of relevant serum

markers. Our hypothesis predicts that osteoblast D2r gene knockout mice will be resistant to both type 1 and type 2 diabetes-induced bone pathology, compared to controls. The high potential impact of the proposal is to definitively identify a critical aspect of an unexpected metabolic relationship that drives a significant bone

complication of both type 1 and type 2 diabetes that we contend will have translational implications for an increasingly important public health problem. Deliverables: A previously unexplored metabolic relationship between the gut and bone that is dysregulated in diabetes will thus be definitively identified and supported by

subjecting a single genetic mouse model to type 2 and type 1 diabetes. Data will point to novel druggable molecular targets. Novel mechanistic insights into diabetic bone disease will be gained.