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Osteoblast Dopamine Receptor Mediates Diabetic Bone Disease

Award Number: R21AR077260
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2021
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $216,711 )
2022	2022	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/7/2022	NON-COMPETING CONTINUATION	$197,010
2022	2022	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/3/2022	NON-COMPETING CONTINUATION	$19,701
														Subtotal = $216,711

Issue Date FY: 2021 ( Subtotal = $262,680 )
2021	2021	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/8/2021	NEW	$262,680
														Subtotal = $262,680

Grand Total All Awards = $479,391

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Osteoblast Dopamine Receptor Mediates Diabetic Bone Disease

Award Number: R21AR077260

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/10/2021

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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