Abstract

The purpose of the proposed studies is to examine the role of somatomedin in skeletal development and pathology.
One specific aim of these studies is to test the hypothesis that the action of growth hormone on skeletal growth is mediated by somatomedin. The cells responsible for skeletal growth are the chondrocytes of the epiphyseal growth plate. Growth plate cell culture, organ culture, and radioligand binding studies will seek to elucidate the effect of GH on these cells in vitro, while stimulation/inhibition studies will seek to separate and analyze the effects of GH and somatomedin-C (Sm-C) in vivo.
A second aim i s to evaluate the role of Sm-C in the regulation of physeal chondrocyte division and maturation. Autoradiographic, cell separation, radioligand and affinity labeling studies will address the hypothesis that these cells differ in their response to Sm-C according to their maturational stage. Also to be tested is the hypothesis that the growth rate of individual physes is a function of the Sc-C binding characteristics of their cells. Thirdly, the role of Sm-C in the normal response to injury by articular cartilage and the question whether Sm-C can enahnce the reparative component of this response will be addressed by in vivo, intra-articular studies in a rabbit model for joint injury. Fourthly, the hypothesis that Sm-C plays a role in the pathophysiology of osteoarthritis will be addressed by autoradiographic, cell isolation and radioligand binding studies comparing normal and osteoarthritic human cartilage. Fifthly, the possibility that certain types of dwarfism may result from defects in Sm-C receptor interactions will be tested by radioligand binding studies of normal and dwarf bovine physeal chondrocytes. The long term objective of these studies is to help achieve a basic understanding of the mechanism of skeletal growth and of joint function in health and disease. Only with such understanding can needed improvements in existing therapy eventually be achieved.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR031068-06
Application #
3155968
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1981-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1988-08-31
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

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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