Over the past several years, new data have accumulated on the lineage and hormonal responsivity of osteoclasts but, with few exceptions, the biochemical mechanisms underlying these phenomena remain poorly understood. The latter gap in information is particularly apparent at the molecular biological level where no literature exists on the isolation, characterization and/or regulation of those genes which define the osteoclast RNA and in identifying several genes (e.g., carbonic anhydrase whose activity appears elevated in osteoclasts relative to related marrow and marrow-derived cells, e.g., macrophages and macrophage multinucleated giant cells. In the present renewal, three major aims are identified that, if attained, should provide significant insight into the gene regulatory mechanisms operational in osteoclasts. The first is to further enlarge the """"""""panel"""""""" of cDNA probes necessary to explore the regulation of gene expression. Such panel enlargement will be achieved using two strategies; in one, previously cloned cDNAs from non-osteoclastic cells or tissues (e.g., human tartrate resistant acid phosphatase) will be used to identify their homologs in chicken osteoclast cDNA libraries; in the other, cDNA clones responding to, as yet, unrecognized osteoclast development/function-related genes will be isolated from osteoclast cDNA libraries by comparative and antibody screening using cDNA probes and monoclonal reagents developed for genes prominently expressed using cDNA probes and monoclonal reagents developed for genes prominently expressed in osteoclasts and related cells.
The second aim i s to determine the pattern of gene expression (i.e., changes in specific mRNA abundance) in differentiating osteoclasts and in osteoclasts responding to select effector substances.
The final aim i s to initiate analysis of the mechanisms underlying the changes in gene expression with a particular focus on transcriptional regulation.
This aim will be achieved using the nuclear runoff technique and the transfection of promoter-reporter gene constructs into osteoclasts and related multinucleated giant cells.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Dentistry
San Francisco
United States
Zip Code
Gazit, D; Zilberman, Y; Turgeman, G et al. (1999) Recombinant TGF-beta1 stimulates bone marrow osteoprogenitor cell activity and bone matrix synthesis in osteopenic, old male mice. J Cell Biochem 73:379-89
Gazit, D; Zilberman, Y; Ebner, R et al. (1998) Bone loss (osteopenia) in old male mice results from diminished activity and availability of TGF-beta. J Cell Biochem 70:478-88
Shi, S; Kirk, M; Kahn, A J (1996) The role of type I collagen in the regulation of the osteoblast phenotype. J Bone Miner Res 11:1139-45
Kirk, M D; Kahn, A J (1995) Extracellular matrix synthesized by clonal osteogenic cells is osteoinductive in vivo and in vitro: role of transforming growth factor-beta 1 in osteoblast cell-matrix interaction. J Bone Miner Res 10:1203-8
Scott, D K; Weaver, W R; Clohisy, J C et al. (1992) Regulation of an H-ras-related transcript by parathyroid hormone in rat osteosarcoma cells. Mol Endocrinol 6:1425-32
Hilliard, T J; Meadows, G; Kahn, A J (1990) Lysozyme synthesis in osteoclasts. J Bone Miner Res 5:1217-22
Perry 3rd, H M; Skogen, W; Chappel, J et al. (1989) Partial characterization of a parathyroid hormone-stimulated resorption factor(s) from osteoblast-like cells. Endocrinology 125:2075-82