Our skeleton provides us with strength and mobility, and it also serves as a major reservoir of inorganic ions. Abnormalities in accumulation of bone mass or other aspects of development of the skeleton, as well as in the remodeling processes that occur throughout adult life, can lead to severe diseases, including osteoporosis and osteopetrosis. Osteoporosis in particular is one of the most important diseases affecting the elderly in the developed world. It is characterized by low bone mass and reduced mineral content. The major clinical consequence of osteoporosis is bone fragility and an increased susceptibility to fractures, which are associated with enormous costs and substantial morbidity and mortality. Knowledge about the molecular pathways controlling bone development and remodeling is thus of major clinical importance. The development of the skeleton and maintenance of proper bone mass and mineralization is regulated by several families of molecules, which include members of the Fibroblast Growth Factor (FGF), Insulin-like Growth Factor (IGF), and Transforming Growth Factor-Beta/Bone Morphogenetic Protein (TGF-Beta/BMP) signaling pathways. However, the mechanisms by which this control is achieved are incompletely understood, and the studies described in this proposal focus on the role of Sprouty2 (Spry2), a member of the Sprouty gene family, in regulation of bone biology. Sprouty genes encode molecules that antagonize signaling by FGF receptors as well as other receptor-tyrosine kinases (RTKs). The experiments in this R03 application are based on our recent finding that mice in which the Spry2 gene has been inactivated have smaller and undermineralized bones. The goal of this application is to build on the preliminary observations that loss of Spry2 function leads to abnormalities in bone in order to gain mechanistic insights into signaling pathways that regulate bone quality.

Public Health Relevance

Abnormal bone mineralization or bone mineral density can lead to severe diseases such as osteoporosis and osteopetrosis. Knowledge about the molecular pathways controlling bone formation and mineralization is thus of major clinical importance. The experiments in this R03 application will enhance our understanding of these pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR057121-03
Application #
8223238
Study Section
Special Emphasis Panel (ZAR1-MLB-G (M1))
Program Officer
Chen, Faye H
Project Start
2010-04-01
Project End
2013-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$74,160
Indirect Cost
$26,160
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Joo, Adriane; Long, Roger; Cheng, Zhiqiang et al. (2016) Sprouty2 regulates endochondral bone formation by modulation of RTK and BMP signaling. Bone 88:170-179