Long bone growth results from a delicately synchronized sequence of events involving the differentiation of three groups of specialized chondrocytes. The ultimate chondrocyte is greatly hypertrophied and is believed to direct the invasion of capillaries and subsequent calcification. In rats that are deficient in vitamin D and phosphate, these events are reversibly altered, capillary invasion is reduced and the growth plate becomes greatly expanded; this model allows for (1) biochemical analysis of the cell types that make up the growth plate and (2) induction of capillary invasion and calcification by treatment with vitamin D and phosphate. The central premise of these studies is that hypertrophic chondrocytes are responsible for directing calcification and, in particular, the directed migration of capillary endothelial cells. The presence of various growth factors known to induce or regulate endothelial cell chemotaxis, such as acidic fibroblast growth factors (aFGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF, transforming growth factor- beta-1 (TGF-beta-1), and endothelial cell stimulating angiogenesis factor (ESAF), will be determined. Studies will be performed on tissues, cell or organ cultures, and co-cultures. Growth factor localization and characterization will be based on the results of endothelial cell chemotaxis assays of extracted tissues and culture media after heparin- Sepharose chromatography, Western blots of isolated growth factors and immunolocalization with specific antibodies. Relative mRNA levels for each growth factor will be determined by Northern analysis. Reversal of rickets (induction of capillary invasion) by vitamin D, its metabolites, and PTH will be used to study growth factor regulation. The overall goal of the research program is to elucidate the final common pathways leading to osteoarthritis (OA) which may be amenable to therapeutic intervention. Articular cartilage injury may initiate a cascade of events that result in increased metalloproteinase production, followed by a change in joint congruity. These changes result in small endochondral growth centers (i.e.: hypertrophic spurs) beneath the articular cartilage which appear very similar to growth plate and which result in a narrowing of the hyaline cartilage. With increased understanding of how growth plate calcification occurs, it is hoped that additional sites for therapeutic intervention in OA will be found.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR008662-27
Application #
3154677
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1974-09-01
Project End
1995-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
27
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
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Bai, G; Howell, D S; Howard, G A et al. (2001) Basic calcium phosphate crystals up-regulate metalloproteinases but down-regulate tissue inhibitor of metalloproteinase-1 and -2 in human fibroblasts. Osteoarthritis Cartilage 9:416-22
Sun, Y; Cheung, J M; Martel-Pelletier, J et al. (2000) Wild type and mutant p53 differentially regulate the gene expression of human collagenase-3 (hMMP-13). J Biol Chem 275:11327-32
Sun, Y; Sun, Y; Wenger, L et al. (1999) p53 down-regulates human matrix metalloproteinase-1 (Collagenase-1) gene expression. J Biol Chem 274:11535-40
Grumbles, R M; Shao, L; Jeffrey, J J et al. (1997) Regulation of the rat interstitial collagenase promoter by IL-1 beta, c-Jun, and Ras-dependent signaling in growth plate chondrocytes. J Cell Biochem 67:92-102
Dean, D D; Schwartz, Z; Muniz, O E et al. (1997) Interleukin-1alpha and beta in growth plate cartilage are regulated by vitamin D metabolites in vivo. J Bone Miner Res 12:1560-9
Grumbles, R M; Shao, L; Jeffrey, J J et al. (1996) Regulation of rat interstitial collagenase gene expression in growth cartilage and chondrocytes by vitamin D3, interleukin-1 beta, and okadaic acid. J Cell Biochem 63:395-409
Grumbles, R M; Howell, D S; Wenger, L et al. (1996) Hepatocyte growth factor and its actions in growth plate chondrocytes. Bone 19:255-61
Masse, P G; Rimnac, C M; Yamauchi, M et al. (1996) Pyridoxine deficiency affects biomechanical properties of chick tibial bone. Bone 18:567-74
Dean, D D; Boyan, B D; Muniz, O E et al. (1996) Vitamin D metabolites regulate matrix vesicle metalloproteinase content in a cell maturation-dependent manner. Calcif Tissue Int 59:109-16

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