Bone matrix is a storehouse of growth factors. Bone is the most abundant source of transforming growth factor beta (TGFbeta), one of the most active bone- derived growth factors in the body. TGFbeta is a multifunctional factor with potent and powerful effects on both osteoblasts and osteoclasts. It has been suggested that TGFbeta acts as a coupling factor that is responsible for initiating new bone formation after previous bone resorption. TGFbeta is stored in bone in a latent, or inactive form. This matrix latent form has not been characterized. The latent complex found in the matrix contains a protein for which several functions have been hypothesized which may be particularly relevant to bone formation. The applicant suggests that her data shows that this protein (called the TGFbeta binding protein; LTBP) is an extracellular matrix protein which, together with TGFbeta, forms fibrillar structures, both in vivo and in vitro. LTBP is necessary for the formation of bone-like mineralized nodules in vitro. The LTBP fibrils appear in culture before, and are distinctly different from, collagen type I fibers and therefore may be one of the earliest expressed proteins in bone formation. In this study, the functional role of LTBP in new bone formation will be examined. The expression of both TGFbeta and LTBP during new bone formation will be compared with expression of other well-known markers of bone cell differentiation such as alkaline phosphatase, osteopontin, and osteocalcin in cultures of fetal rat calvarial cells. The effects of osteotropic factors, namely parathyroid hormone, bone morphogenetic protein 2 and TGFbeta, on TGFbeta and LTBP expression will also be examined. The mechanisms whereby latent TGFbeta is targeted to bone, and the molecular and cellular mechanisms whereby latent and active TGFbeta are released from bone will be investigated. Synthetic peptides which block LTBP fibril formation and consequently bone formation will be developed. Dominant-negative LTBP constructs will be designed and tested. Understanding these mechanisms may lend insight into the interactions between osteoclasts and osteoblasts during bone remodeling, and into the mechanisms of normal osteoblastic bone formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043775-03
Application #
2732877
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1996-07-19
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Dallas, S L; Zhao, S; Cramer, S D et al. (2005) Preferential production of latent transforming growth factor beta-2 by primary prostatic epithelial cells and its activation by prostate-specific antigen. J Cell Physiol 202:361-70
Bonewald, L F; Harris, S E; Rosser, J et al. (2003) von Kossa staining alone is not sufficient to confirm that mineralization in vitro represents bone formation. Calcif Tissue Int 72:537-47
Boyan, Barbara D; Bonewald, Lynda F; Sylvia, Victor L et al. (2002) Evidence for distinct membrane receptors for 1 alpha,25-(OH)(2)D(3) and 24R,25-(OH)(2)D(3) in osteoblasts. Steroids 67:235-46
Dallas, Sarah L; Rosser, Jennifer L; Mundy, Gregory R et al. (2002) Proteolysis of latent transforming growth factor-beta (TGF-beta )-binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. J Biol Chem 277:21352-60
Boyan, B D; Bonewald, L F; Paschalis, E P et al. (2002) Osteoblast-mediated mineral deposition in culture is dependent on surface microtopography. Calcif Tissue Int 71:519-29
Kato, Y; Boskey, A; Spevak, L et al. (2001) Establishment of an osteoid preosteocyte-like cell MLO-A5 that spontaneously mineralizes in culture. J Bone Miner Res 16:1622-33
Dallas, S L; Keene, D R; Bruder, S P et al. (2000) Role of the latent transforming growth factor beta binding protein 1 in fibrillin-containing microfibrils in bone cells in vitro and in vivo. J Bone Miner Res 15:68-81
Lohmann, C H; Bonewald, L F; Sisk, M A et al. (2000) Maturation state determines the response of osteogenic cells to surface roughness and 1,25-dihydroxyvitamin D3. J Bone Miner Res 15:1169-80
Bonewald, L F (1999) Regulation and regulatory activities of transforming growth factor beta. Crit Rev Eukaryot Gene Expr 9:33-44
Pedrozo, H A; Schwartz, Z; Robinson, M et al. (1999) Potential mechanisms for the plasmin-mediated release and activation of latent transforming growth factor-beta1 from the extracellular matrix of growth plate chondrocytes. Endocrinology 140:5806-16

Showing the most recent 10 out of 11 publications