Bone remodeling is regulated by systemic and local factors. Pioneer investigations from our laboratory revealed that bone cells secrete growth factors that have important effects on bone formation. These factors are likely to act as autologous regulators of bone metabolism and to interact with systemic hormones which regulate the synthesis or receptor binding of the local growth factor. Recently, we found that osteoblast enriched (Ob) cells from 22-day fetal rat calvariae express mRNA encoding the PDGF A, and not the @PDGF B polypeptide, but the regulation of skeletal PDGF A synthesis has not been examined. In addition, Ob cells express receptors for PDGF A and B, and are mitogenically responsive to PDGF AA and BB. The binding of PDGF AA, but not of PDGF BB, to Ob cells, and the mitogenic activity of PDGF AA were found to be increased by interleukin 1. This work needs to be extended to other agents and determine which regulate the binding and activity of PDGF AA and BB and the actions of PDGF in Ob cell cultures.
The first aim of the proposed work is to study the regulation of PDGF A synthesis by hormones and growth factors in cultured Ob cells. This will be done by examining effects on PDGF AA concentrations, using a specific radioimmunoassay, and on PDGF A mRNA expression using a rat PDGF A cDNA clone and specific oligonucleotide probes. We also plan to determine, in a more definitive fashion, whether PDGF B mRNA can be detected or induced in bone cell cultures.
The second aim of the investigations is to fully characterize the receptors for PDGF A and B in Ob cells using Scatchard analysis and cross-linking/gel electrophoresis techniques; this will allow us to define the regulation of PDGF binding, by hormones and growth factors.
The third aim i s to examine the PDGF effect on bone formation, using bone histomorphometric analysis, define the role of PDGF AA as an autocrine regulator of bone formation, and determine whether agents that regulate PDGF binding modify its biological actions on bone formation. This work is valuable because PDGF has important effects on bone cell function and it is our hypothesis that the synthesis of PDGF by bone cells and the binding to its receptors, is regulated by hormones and other growth factors. Through these two mechanisms, hormones and factors could modify the activity of PDGF in bone. Our current understanding of bone cell physiology and metabolic bone disease is limited, and this research may provide future therapeutic alternatives for fracture repair and metabolic bone disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Sharrock, William J
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St. Francis Hospital and Medical Center
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Zanotti, Stefano; Kalajzic, Ivo; Aguila, Hector Leonardo et al. (2014) Sex and genetic factors determine osteoblastic differentiation potential of murine bone marrow stromal cells. PLoS One 9:e86757
Canalis, Ernesto; Zanotti, Stefano; Smerdel-Ramoya, Anna (2014) Connective tissue growth factor is a target of notch signaling in cells of the osteoblastic lineage. Bone 64:273-80
Canalis, Ernesto (2013) Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat Rev Endocrinol 9:575-83
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Canalis, Ernesto; Zanotti, Stefano; Beamer, Wesley G et al. (2010) Connective tissue growth factor is required for skeletal development and postnatal skeletal homeostasis in male mice. Endocrinology 151:3490-501

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