Virtually all skeletal growth is the result of the orderly division and maturation of the cells of the epiphyseal growth plate. Normal skeletal development is dependent on the proper control of this process. This proposal is based on the applicants' previous observations that peptide growth factors participate in this control. The goal of the proposed studies is to elucidate the mechanisms by which selected growth factors regulate growth plate chondrocytes. The investigators hypothesize that growth factor interaction plays an important role in the regulation of growth plate chondrocytes.
One aim of these studies is to test this hypothesis by examining the individual and interactive effects of selected growth factors with respect to mitotic and differentiated chondrocyte functions in vitro. Cell culture, metabolic labelling, radioimmunoassay, immunoinhibition, Northern and in situ hybridization methods will be used to identify interactions and begin to elucidate their mechanisms.
The second aim i s to test the postulate that the effects of the calciotropic hormones, calcitonin and PTH, on growth plate chondrocytes are modulated by peptide growth factors. Specifically, regulation of chondrocyte PTH receptor and calcitonin receptor expression by selected growth factors will be examined by cell biological and molecular biological techniques.
The third aim i s to assess the ability of exogenously administered growth factors to regulate skeletal growth in vivo.Using a rat model, the action and interaction of selected factors will be evaluated by metabolic and in situ hybridization techniques. The long-term objective of these studies is to help achieve a basic understanding of the mechanisms regulating skeletal growth. Only with such information can abnormalities of skeletal growth and repair be understood and the potential contribution of growth factors to clinical problems eventually be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR031068-11A1
Application #
2078754
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1981-09-01
Project End
1998-08-31
Budget Start
1994-09-30
Budget End
1995-08-31
Support Year
11
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Takahashi, Toshiaki; Morris, Elisabeth A; Trippel, Stephen B (2007) Bone morphogenetic protein-2 and -9 regulate the interaction of insulin-like growth factor-I with growth plate chondrocytes. Int J Mol Med 20:53-7
Madry, H; Kaul, G; Cucchiarini, M et al. (2005) Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I). Gene Ther 12:1171-9
Madry, Henning; Emkey, Greg; Zurakowski, David et al. (2004) Overexpression of human fibroblast growth factor 2 stimulates cell proliferation in an ex vivo model of articular chondrocyte transplantation. J Gene Med 6:238-45
Madry, Henning; Cucchiarini, Magali; Stein, Ute et al. (2003) Sustained transgene expression in cartilage defects in vivo after transplantation of articular chondrocytes modified by lipid-mediated gene transfer in a gel suspension delivery system. J Gene Med 5:502-9
Madry, Henning; Cucchiarini, Magali; Terwilliger, Ernest F et al. (2003) Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum Gene Ther 14:393-402
Madry, Henning; Padera, Robert; Seidel, Joachim et al. (2002) Gene transfer of a human insulin-like growth factor I cDNA enhances tissue engineering of cartilage. Hum Gene Ther 13:1621-30
Bonassar, L J; Grodzinsky, A J; Frank, E H et al. (2001) The effect of dynamic compression on the response of articular cartilage to insulin-like growth factor-I. J Orthop Res 19:11-7
Madry, H; Zurakowski, D; Trippel, S B (2001) Overexpression of human insulin-like growth factor-I promotes new tissue formation in an ex vivo model of articular chondrocyte transplantation. Gene Ther 8:1443-9
Madry, H; Trippel, S B (2000) Efficient lipid-mediated gene transfer to articular chondrocytes. Gene Ther 7:286-91
Bonassar, L J; Grodzinsky, A J; Srinivasan, A et al. (2000) Mechanical and physicochemical regulation of the action of insulin-like growth factor-I on articular cartilage. Arch Biochem Biophys 379:57-63

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