Abstract

We have engineered a null mutation (knockout) in the MMP-13 gene that encodes a collagenase predominantly expressed in the Skeleton. MMP-13 null (-/-) mice have a striking skeletal phenotype with abnormal growth plates and delayed ossification during embryonic development and, after birth, increased deposition of trabecular bone due to decreased osteoclast and increased osteoblast function. We had previously targeted a mutation to Col1a1 (r/r mice) that that results in complete resistance to collagenase cleavage in helical domain of type I collagen. The phenotype of the r/r mice differs in several respects from that of the MMP-13 null mice. Our goals here are to define the mechanisms for these biological effects. We will evaluate skeletal cell function in these models in vivo and ex vivo and explore related animal models.
Specific Aim 1 : Investigate mechanisms that underlie the abnormal skeletal phenotype of the MMP-13 -/- (knockout) mice using in vivo and ex vivo. In vivo, we will further explore the phenotype of the MMP-13 -/- mice using procedures that perturb skeletal remodeling. Ex vivo, we will examine osteoblast and osteoclast differentiation and function pertinent to understanding the phenotype in the MMP-13 -/- mice.
Specific Aim 2 : Investigate mechanisms that underlie the abnormal skeletal and extraskeletal phenotype of the collagenase-resistant (r/r) mice. MMP-13 makes additional unique cleavages in the N-telopeptide of type I collagen. Here, we will cross the r/r mice with the MMP-13 -/- mice, analyze the in vivo phenotype and examine skeletal cell differentiation/function ex vivo. These studies will identify roles of MMP-13 other than proteolysis of helical type 1 collagen.
Specific Aim 3 : Determine the role of other MMPs in murine skeletal development and remodeling by examining other in vivo models. We will analyze the skeletal and extraskeletal phenotype of mice with a null mutation in the """"""""neutrophil"""""""" collagenase, MMP-8, another collagenase expressed in the skeleton, as well as mice with double null MMP-8/MMP-13.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044815-09
Application #
7247270
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Wang, Yan Z
Project Start
1998-07-20
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
9
Fiscal Year
2007
Total Cost
$352,258
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Sounni, Nor E; Dehne, Kerstin; van Kempen, Leon et al. (2010) Stromal regulation of vessel stability by MMP14 and TGFbeta. Dis Model Mech 3:317-32
Krane, Stephen M; Inada, Masaki (2008) Matrix metalloproteinases and bone. Bone 43:7-18
Krane, Stephen M (2008) The importance of proline residues in the structure, stability and susceptibility to proteolytic degradation of collagens. Amino Acids 35:703-10
Gutierrez-Fernandez, Ana; Inada, Masaki; Balbin, Milagros et al. (2007) Increased inflammation delays wound healing in mice deficient in collagenase-2 (MMP-8). FASEB J 21:2580-91
Deguchi, Jun-O; Aikawa, Elena; Libby, Peter et al. (2005) Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques. Circulation 112:2708-15
Jung, Jae-Chang; West-Mays, Judith A; Stramer, Brian M et al. (2004) Activity and expression of Xenopus laevis matrix metalloproteinases: identification of a novel role for the hormone prolactin in regulating collagenolysis in both amphibians and mammals. J Cell Physiol 201:155-64
Inada, Masaki; Wang, Yingmin; Byrne, Michael H et al. (2004) Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci U S A 101:17192-7
Mehrotra, Meenal; Krane, Stephen M; Walters, Kristen et al. (2004) Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells. J Cell Biochem 93:741-52
Chiusaroli, R; Maier, A; Knight, M C et al. (2003) Collagenase cleavage of type I collagen is essential for both basal and parathyroid hormone (PTH)/PTH-related peptide receptor-induced osteoclast activation and has differential effects on discrete bone compartments. Endocrinology 144:4106-16
Lindsey, Merry L; Yoshioka, Jun; MacGillivray, Catherine et al. (2003) Effect of a cleavage-resistant collagen mutation on left ventricular remodeling. Circ Res 93:238-45

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