Bone is a dynamic organ which undergoes a balanced, ongoing reorganization requiring both bone formation (anabolism) and bone resorption (catabolism). The interplay between these two processes is referred to as coupling. In bone, insulin-like growth factors (IGF-I and IGF-II) are important mitogens in bone formation. These growth factors' actions are, however, modulated by high affinity IGF-binding proteins (IGFBP 1-6). Recent data shows that when bound to soluble IGFBPs, IGFs are unable to interact with their cell surface receptors. In contrast, when IGFBPs are degraded by proteinases or when they are complexed with matrix molecules, their affinity for IGFs is lowered, making IGFs available to interact with cell surface type I IGF receptors. We hypothesize that the interplay between IGFBP-degrading proteinases and IGF/IGFBP complexes plays an integral role in the process of bone coupling. For instance, many of the proteinases involved in bone resorption, such as matrix metalloproteinases (MMPs), also degrade IGFBPs. Degradation of IGFBPs, in turn, results in the release IGFs to function as anabolic agents in bone formation. The overall objective of this proposal is to clarify which proteinases are involved in the degradation of two important bone-derived IGFBPs, IGFBP-4 and IGFBP-5, and to determine their overall contribution to the anabolic actions of IGFs in bone cells. The proposed studies are designed to a) understand the roles of MMPs on IGFBP-5 degradation and how degradation of this IGFBP affects IGF bioavailability in osteoblasts; b) clarify the role of the novel L56 proteinase in IGFBP-4 degradation and define the factors which regulate its production and activity in bone; and c) utilize new methodologies to identify and clone novel IGFBP-degrading proteinases in human bone. A better understanding of the proteinases involved in IGFBP degradation and their physiologic role in IGF action will allow for development of therapeutic interventions to enhance bone formation by increasing IGF biovailability or by decreasing bone resorption in a variety of bone disorders such as osteoporosis and metabolic bone diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055653-02
Application #
6177453
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Margolis, Ronald N
Project Start
1999-06-15
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
2
Fiscal Year
2000
Total Cost
$223,444
Indirect Cost
Name
University of Kentucky
Department
Pediatrics
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Iyer, Srividhya; Han, Li; Ambrogini, Elena et al. (2017) Deletion of FoxO1, 3, and 4 in Osteoblast Progenitors Attenuates the Loss of Cancellous Bone Mass in a Mouse Model of Type 1 Diabetes. J Bone Miner Res 32:60-69
Thrailkill, Kathryn M; Nyman, Jeffry S; Bunn, R Clay et al. (2017) The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes. Bone 94:141-151
Thrailkill, Kathryn M; Clay Bunn, R; Nyman, Jeffry S et al. (2016) SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice. Bone 82:101-7
Kalaitzoglou, Evangelia; Popescu, Iuliana; Bunn, R Clay et al. (2016) Effects of Type 1 Diabetes on Osteoblasts, Osteocytes, and Osteoclasts. Curr Osteoporos Rep 14:310-319
Fowlkes, John L; Nyman, Jeffry S; Bunn, R Clay et al. (2015) Effects of long-term doxycycline on bone quality and strength in diabetic male DBA/2J mice. Bone Rep 1:16-19
Thrailkill, Kathryn M; Fowlkes, John L (2013) The role of vitamin D in the metabolic homeostasis of diabetic bone. Clin Rev Bone Miner Metab 11:28-37
Fowlkes, John L; Nyman, Jeffry S; Bunn, R Clay et al. (2013) Osteo-promoting effects of insulin-like growth factor I (IGF-I) in a mouse model of type 1 diabetes. Bone 57:36-40
Fowlkes, John L; Bunn R, Clay; Thrailkill, Kathryn M (2011) Contributions of the Insulin/Insulin-Like Growth Factor-1 Axis to Diabetic Osteopathy. J Diabetes Metab 1:
Fowlkes, John L; Bunn, R Clay; Cockrell, Gael E et al. (2011) Dysregulation of the intrarenal vitamin D endocytic pathway in a nephropathy-prone mouse model of type 1 diabetes. Exp Diabetes Res 2011:269378
Nyman, Jeffry S; Even, Jesse L; Jo, Chan-Hee et al. (2011) Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. Bone 48:733-40

Showing the most recent 10 out of 19 publications