The regulation of osteoclastic bone resorption is a precise, complex process involving a number of mediators and cell types. Osteoblasts are among the major cells responsible for both recruitment and activation of osteoclasts. They act in a variety of ways to effect osteoclast development. This proposal uses 3 different osteopetrotic mutation in the rat, with known reductions in bone resorption and aberrations in osteoblast gene expression, bone matrix components and bone cell proliferation, to explore the regulation of bone resorption by osteoblasts and bone matrix constituents.
Our specific aims are to determine the relationships of the osteoblast and osteoclast abnormalities in these 3 mutations, to characterize and quantitate protein synthesis and its regulation in mutant osteoblasts, to determine the ability of mutant osteoblasts and matrix products to recruit and direct differentiation and function of normal osteoclasts and to evaluate the role of the cytokine M-CSF in osteoblast and osteoclast function. To this end we will use cure of the disease in mutants and induction of the disease in normal littermates as mechanisms to perturb and follow osteoblast and osteoclast function by molecular techniques; mRNA levels of osteoblast-specific genes, +/- cDNA library screening and subtractive hybridization to detect unique genes of the osteopetrotic phenotype, and PCR amplification to dissect aberrant genes by nucleotide analyses. Osteoblast gene expression and its hormonal regulation will be compared in cultures of mutant and normal osteoblasts and metatarsal cultures and bone slices will be used to analyze the ability of mutant bone matrix and osteoblasts to direct osteoclast differentiation and function, respectively. Finally, the ability of M-CSF gene expression in this mutation, and to study the role of this cytokine in skeletal development by in situ hybridization. Future studies will be directed toward gene therapy for this mutation. These studies are expected to provide insights into the cellular and molecular bases for the regulation of bone resorption and have application in situations where selective regional or general reductions or accelerations of bone resorption are desirable.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DE007444-10
Application #
2129832
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1986-03-01
Project End
1997-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
10
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Meier, Julia C; Tallant, Cynthia; Fedorov, Oleg et al. (2017) Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation. ACS Chem Biol 12:2619-2630
Witwicka, Hanna; Jia, Hong; Kutikov, Artem et al. (2015) TRAFD1 (FLN29) Interacts with Plekhm1 and Regulates Osteoclast Acidification and Resorption. PLoS One 10:e0127537
Odgren, Paul R; Pratt, Craig H; Mackay, Carole A et al. (2010) Disheveled hair and ear (Dhe), a spontaneous mouse Lmna mutation modeling human laminopathies. PLoS One 5:e9959
Gartland, Alison; Mason-Savas, April; Yang, Meiheng et al. (2009) Septoclast deficiency accompanies postnatal growth plate chondrodysplasia in the toothless (tl) osteopetrotic, colony-stimulating factor-1 (CSF-1)-deficient rat and is partially responsive to CSF-1 injections. Am J Pathol 175:2668-75
Perdu, B; Odgren, P R; Van Wesenbeeck, L et al. (2009) Refined genomic localization of the genetic lesion in the osteopetrosis (op) rat and exclusion of three positional and functional candidate genes, Clcn7, Atp6v0c, and Slc9a3r2. Calcif Tissue Int 84:355-60
Yang, Meiheng; Birnbaum, Mark J; MacKay, Carole A et al. (2008) Osteoclast stimulatory transmembrane protein (OC-STAMP), a novel protein induced by RANKL that promotes osteoclast differentiation. J Cell Physiol 215:497-505
Van Wesenbeeck, Liesbeth; Odgren, Paul R; Coxon, Fraser P et al. (2007) Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 117:919-30
Arnott, J A; Nuglozeh, E; Rico, M C et al. (2007) Connective tissue growth factor (CTGF/CCN2) is a downstream mediator for TGF-beta1-induced extracellular matrix production in osteoblasts. J Cell Physiol 210:843-52
Yang, Meiheng; Mailhot, Genevieve; Birnbaum, Mark J et al. (2006) Expression of and role for ovarian cancer G-protein-coupled receptor 1 (OGR1) during osteoclastogenesis. J Biol Chem 281:23598-605
Yang, Meiheng; Mailhot, Genevieve; MacKay, Carole A et al. (2006) Chemokine and chemokine receptor expression during colony stimulating factor-1-induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1gamma) in osteoclastogenesis in vivo and in vitro. Blood 107:2262-70

Showing the most recent 10 out of 107 publications