Abstract

The principal investigator, Nicola Partridge, Ph.D., proposes to examine the mechanism of the binding, internalization and degradation of the resorptive enzyme, collagenase-3 (a.k.a., metalloproteinase 13, MMP-13) following its elaboration from the osteoblast during resorption. It is hypothesized that there is a specific receptor, the collagenase-3 receptor, which binds to collagenase-3, resulting in endocytosis that triggers a further interaction of collagenase-3 with the low-density lipoprotein receptor-related protein (LRP). The precise concentration, and hence, the biological activity of MMP-3 depends on a balance between its secretion and its receptor-mediated uptake. Based upon preliminary data that the putative receptor may be a novel lectin, the applicant proposes four Specific Aims. First, she proposes to express and examine the regulation of the collagenase-3 receptor. Secondly, she proposes to mutate the receptor to determine its functional domains that interact with collagenase-3. Thirdly, she will study the interaction of the collagenase-3 molecule with LRP. Finally, she proposes to determine the domains of the collagenase-3 molecule that bind the collagenase-3 receptor and the LRP receptor. Critical new information on the biology of this important molecule may be derived from these studies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR040661-09A1
Application #
6130936
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
1991-02-01
Project End
2004-06-30
Budget Start
2000-07-15
Budget End
2001-06-30
Support Year
9
Fiscal Year
2000
Total Cost
$228,435
Indirect Cost

  Institution

Name
University of Medicine & Dentistry of NJ
Department
Physiology
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854

  Publications

Raggatt, L J; Jefcoat Jr, S C; Choudhury, I et al. (2006) Matrix metalloproteinase-13 influences ERK signalling in articular rabbit chondrocytes. Osteoarthritis Cartilage 14:680-9
Walling, H W; Raggatt, L J; Irvine, D W et al. (2003) Impairment of the collagenase-3 endocytotic receptor system in cells from patients with osteoarthritis. Osteoarthritis Cartilage 11:854-63
Partridge, N C; Fiacco, G J; Walling, H W et al. (2000) Effects of dioxin and estrogen on collagenase-3 in UMR 106-01 osteosarcoma cells. Arch Biochem Biophys 382:182-8
Barmina, O Y; Walling, H W; Fiacco, G J et al. (1999) Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization. J Biol Chem 274:30087-93
Walling, H W; Chan, P T; Omura, T H et al. (1998) Regulation of the collagenase-3 receptor and its role in intracellular ligand processing in rat osteoblastic cells. J Cell Physiol 177:563-74
Partridge, N C; Walling, H W; Bloch, S R et al. (1996) The regulation and regulatory role of collagenase in bone. Crit Rev Eukaryot Gene Expr 6:15-27
Clohisy, J C; Connolly, T J; Bergman, K D et al. (1994) Prostanoid-induced expression of matrix metalloproteinase-1 messenger ribonucleic acid in rat osteosarcoma cells. Endocrinology 135:1447-54
Cook, T F; Burke, J S; Bergman, K D et al. (1994) Cloning and regulation of rat tissue inhibitor of metalloproteinases-2 in osteoblastic cells. Arch Biochem Biophys 311:313-20
Connolly, T J; Clohisy, J C; Shilt, J S et al. (1994) Retinoic acid stimulates interstitial collagenase messenger ribonucleic acid in osteosarcoma cells. Endocrinology 135:2542-8
Omura, T H; Noguchi, A; Johanns, C A et al. (1994) Identification of a specific receptor for interstitial collagenase on osteoblastic cells. J Biol Chem 269:24994-8

Showing the most recent 10 out of 11 publications