The purpose of this project is to examine the role of the monocyte-macrophage system and related cells in the bone resportion process. Local bone remodeling is influenced by interactions which occur between bone cells, the bone microenvironment, monocytes and lymphocytes. In vitro systems will be used to study the factors involved in the differentiation or activation of osteoclasts. Recently, we have found that highly purified or recombinant lymphokines and monokines are capable of stimulating osteoclastic bone resportion in vitro. These cytokines which stimulate bone resorption (lymphotoxin, tumor necrosis factor and interleukin-1) and another lymphokine which inhibits bone resorption (gamma interferon) will be studied and their effects on bones in organ culture fully characterized. We will evaluate the effects of gamma interferon on osteoclastic bone resorption stimulated by the OAFS since this lymphokine appears to specifically inhibit bone resorption stimulated by these factors. We will clarify the relationships between these cytoklines and the activity formerly referred to as osteoclast activating factor using monoclonal and polyclonal antibodies to the cytokines which block their biological effects on bone. We will assess the effects of recombinant lymphotoxin and tumor necrosis factor on calcium homeostasis in vivo using intact and parathyroidectomized rats. We will evaluate the effects of these recombinant cytokines on osteoclast progenitor cells using the modified Dexter marrow culture system in which osteoclast-like cells form in vitro. We will assess the effects of these cytokines on bone formation in vitro using organ cultures of fetal rat calvaria. It is our contention that studies on these local factors which are produced in the bone microenvironment will be necessary for our understanding of the local factors which normally control trabecular bone volume and normal bone remodeling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR028149-13
Application #
3481539
Study Section
Special Emphasis Panel (NSS)
Project Start
1980-07-01
Project End
1996-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
13
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Mundy, G R; Chen, D; Zhao, M et al. (2001) Growth regulatory factors and bone. Rev Endocr Metab Disord 2:105-15
Ghosh-Choudhury, N; Choudhury, G G; Harris, M A et al. (2001) Autoregulation of mouse BMP-2 gene transcription is directed by the proximal promoter element. Biochem Biophys Res Commun 286:101-8
Ji, X; Chen, D; Xu, C et al. (2000) Patterns of gene expression associated with BMP-2-induced osteoblast and adipocyte differentiation of mesenchymal progenitor cell 3T3-F442A. J Bone Miner Metab 18:132-9
Dunstan, C R; Boyce, R; Boyce, B F et al. (1999) Systemic administration of acidic fibroblast growth factor (FGF-1) prevents bone loss and increases new bone formation in ovariectomized rats. J Bone Miner Res 14:953-9
Nishimura, R; Moriyama, K; Yasukawa, K et al. (1998) Combination of interleukin-6 and soluble interleukin-6 receptors induces differentiation and activation of JAK-STAT and MAP kinase pathways in MG-63 human osteoblastic cells. J Bone Miner Res 13:777-85
Mundy, G R (1997) Growth factors as potential therapeutic agents in osteoporosis. Instr Course Lect 46:495-8
Mundy, G R (1996) Osteoporosis into the year 2010. Br J Obstet Gynaecol 103 Suppl 13:32-7;discussion 37-8
Mundy, G R (1996) Regulation of bone formation by bone morphogenetic proteins and other growth factors. Clin Orthop Relat Res :24-8
Mundy, G R (1995) Local control of bone formation by osteoblasts. Clin Orthop Relat Res :19-26
Guise, T A; Mundy, G R (1995) Clinical review 69: Evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab 80:1473-8

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