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Faculty Carol C. Pilbeam
Professor of Medicine
pilbeam@nso.uchc.edu
Areas of Interest:
1. Regulation and function of cyclooxygenase-2 (COX-2, also called
prostaglandin G/H synthase-2 or PGHS-2) in bone. COX-2 is an early
response gene that is responsible for most prostaglandin regulation in
bone. Specific studies ongoing in our lab include examination of
transcriptional regulation of COX-2 in osteoblastic MC3T3-E1 cells and
in COX-2 promoter-luciferase reporter transgenic mice and examination of
the effects of COX-2 gene disruption on bone resorption and formation.
We are particularly interested in the role of COX-2 in osteoblast
proliferation and apoptosis.
2. Role of COX-2 in the osteoblastic response to mechanical loading.
COX-2 may mediate effects of mechanical loading on bone. We are studying
fluid shear stress induction of COX-2 expression--signaling pathways and
transactivating factors involved. We are developing in vivo models of
loading and unloading of bone and are making mice with the COX-2
promoter fused to GFP to permit localization of cells in which loading
upregulates COX-2 transcription.
Lab Rotation Projects:
Our lab studies bone biology with specific interest in the role of
cyclooxygenase-2 (COX-2) in bone formation and resorption, regulation of
bone resorption and formation by mechanical loading, and role of COX-2
in cancer. Models range from cell cultures to transgenic mice. Possible
student projects include the following:
1. Regulation of COX-2 by mechanical loading (modeled by fluid
shear stress) in osteoblasts (bone-forming cells) or in ulnae of mice
loaded in vivo. Studies include gene expression, signaling pathways,
transcriptional regulation and regulation of the 3'-UTR of COX-2.
2. Regulation of the interstitial collagenase, MMP-13,
promoter by mechanical loading (fluid shear stress) in osteoblasts. This
study would require making MMP-13 promoter - luciferase reporter (or GFP
reporter) constructs.
3. Examination of one or more early response genes identified
by microarray analysis (approximately 20 genes out of more than 12,000
genes) as upregulated by 5 min of FSS applied to osteoblasts. Expression
needs to be confirmed by Northern and/or Western analysis. Signaling
pathways involved in the induction of expression could be examined.
4. Role of COX-2 in cell proliferation and apoptosis. This
study involve BrdU staining, 3thymidine incorporation, and flow
cytometry for cell cycle analysis. Apoptosis is measured by flow
cytometry and TUNEL staining, as well as caspase activity.
Selected Publications:
Pilbeam CC, Harrison J, Raisz LG. Prostaglandins and Leukotrienes. In
"Principles of Bone Biology", J. Bilezikian, L. Raisz, and G. Rodan,
eds., Academic Press, New York, second edition, 2002, pp 874-994.
Wadhwa S, Godwin SL, Peterson DR, Epstein MA, Pilbeam CC. Fluid flow
induction of cyclooxygenase-2 gene expression in osteoblasts depends on
the ERK signaling pathway. J Bone Miner Res, 17:266-274,2002.
Chikazu D, Li X, Kawaguch H, Hoshi K, Voznesensky OS, Herschman HR,
Raisz LG, Pilbeam CC. Bone morphogenetic protein-2 induces
cyclooxygenase-2 in osteoblasts via Cbfa1: role in osteoblast and
osteoclast differentiation. J Bone Miner Res 17:1430-1440,2002.
Wadhwa S, Choudhary S, Voznesensky M, Epstein M, Raisz L, Pilbeam C.
Fluid flow induces COX-2 expression in MC3T3-E1 osteoblasts via a PKA
signaling pathway. Biochem Biophys Res Commun 297:46-51,2002.
Okada Y, Lorenzo JA, Freeman AM, Tomita M, Morham SG, Raisz LG,
Pilbeam CC. Prostaglandin G/H synthase-2 is required for maximal
stimulation of osteoclast-like cell formation in murine marrow and
spleen cultures. J Clin Invest 105:823-832,2000.
Okada Y, Voznesensky O, Herschman H, Harrison, Pilbeam C.
Identification of multiple cis-acting elements mediating the induction
of prostaglandin G/H synthase-2 by phorbol ester in murine osteoblastic
cells. J Cell Biochem 78:197-209,2000.
Li X, Okada Y, Pilbeam CC, Lorenzo JA, Kennedy CRJ, Breyer RM, Raisz
LG. Knockout of the murine prostaglandin EP2 receptor impairs
osteoclastogenesis in vitro. Endocrinology 141:2054-2061,2000. |
