Endochondral ossification is a pivotal event in skeletal development and in adult skeletal regeneration. In both, osteoclasts and chondroclasts erode hypertrophic cartilage, hypertrophic chondrocyte die, blood vessels grow in followed by recruitment of osteoprogenitor cells and bone and bone marrow cavity formation. These events require extracellular proteolysis and are essential for normal bone formation and repair. The goal of this proposal is to elucidate the molecular and cellular mechanisms, controlled by matrix metalloproteinases (MMPs), that co-ordinate the events in endochondral bone formation and regeneration. In the previous funding period we showed that proteolysis by MMP-9 is a critical determinant of the events in endochondral bone formation. MMP-9 and vascular endothelial growth factor (VEGF) act in overlapping pathways to regulate the program of hypertrophic cartilage remodeling, angiogenesis and bone formation in growth plate development and skeletal regeneration. We now propose to use genetic, molecular and cell Diological approaches to further characterize how these two MMPs, each separately and together, regulate the program of endochondral bone development. We will use targeted and conditional mutations in mice to evaluate the relative roles various cell types expressing MMP-9 and MMP-13 (collagenase-3) to cartilage emodeling, osteoblast and osteoclast function, vascular recruitment and skeletal remodeling, using morphometric and biochemical approaches coupled with cell and organotypic cultures. From these studies we will be able to determine the steps in skeletal growth plate morphogenesis. We will focus on terminal differentiation of hypertrophic chondrocytes, extracellular matrix remodeling, regulation of vascular recruitment and bone remodeling. We will then use the MMP mutant mice and unstable and stabilized fractures as tools to evaluate how the mechanical environment determines the regenerative response during in skeletal regeneration in wild type and mutant mice. We will then build on these analyses to determine the physiologic substrates of the MMPs during development and skeletal repair. These studies will give us insights into novel and important functions for the MMPs, extracellular matrix proteins and angiogenic regulators in endochondral bone formation. The endochondral ossification processes are misregulated in osteparthritis and recalcitrant hard tissue lesions. A fuller understanding of the central role of angiogenesis gjnd its regulation by proteolysis in these processes may have implications for therapeutic interventions and the development of therapy for certain types of non-healing fractures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046238-09
Application #
7568909
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Wang, Fei
Project Start
1999-09-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
9
Fiscal Year
2009
Total Cost
$323,443
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Napoli, Nicola; Schwartz, Ann V; Palermo, Lisa et al. (2013) Risk factors for subtrochanteric and diaphyseal fractures: the study of osteoporotic fractures. J Clin Endocrinol Metab 98:659-67
Wang, Xiaodong; Yu, Yan Yiu; Lieu, Shirley et al. (2013) MMP9 regulates the cellular response to inflammation after skeletal injury. Bone 52:111-9
Napoli, Nicola; Jin, Jenny; Peters, Katherine et al. (2012) Are women with thicker cortices in the femoral shaft at higher risk of subtrochanteric/diaphyseal fractures? The study of osteoporotic fractures. J Clin Endocrinol Metab 97:2414-22
Lieu, Shirley; Hansen, Erik; Dedini, Russell et al. (2011) Impaired remodeling phase of fracture repair in the absence of matrix metalloproteinase-2. Dis Model Mech 4:203-11
Tranah, Gregory J; Blackwell, Terri; Stone, Katie L et al. (2011) Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann Neurol 70:722-32
Tranah, Gregory J; Parimi, Neeta; Blackwell, Terri et al. (2010) Postmenopausal hormones and sleep quality in the elderly: a population based study. BMC Womens Health 10:15
Tranah, Gregory J; Blackwell, Terri; Ancoli-Israel, Sonia et al. (2010) Circadian activity rhythms and mortality: the study of osteoporotic fractures. J Am Geriatr Soc 58:282-91
Ortega, Nathalie; Wang, Ke; Ferrara, Napoleone et al. (2010) Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation. Dis Model Mech 3:224-35
Little, C B; Barai, A; Burkhardt, D et al. (2009) Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 60:3723-33
Tranah, Gregory J; Taylor, Brent C; Lui, Li-Yung et al. (2008) Genetic variation in candidate osteoporosis genes, bone mineral density, and fracture risk: the study of osteoporotic fractures. Calcif Tissue Int 83:155-66

Showing the most recent 10 out of 41 publications