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 Research
Interest:
Signal transduction, molecular endocrinology, transcriptional
regulation, metalloproteinases
Description:
We have shown that parathyroid hormone (PTH) induces
the transcription of many genes in osteoblastic cells. This
involves the protein kinase A (PKA) pathway. One gene whose
transcription we have studied in-depth is collagenase-3.
This requires induction of activator protein-1 (AP-1) transcription
factors as well as phosphorylation of another transcription
factor, core binding factor a1 (Cbfa1). Thus, PTH regulates
both transcription factors through PKA, either by increasing
their expression or altering their phosphorylation. We now
know that PTH regulates nucleosomal structure, probably
by phosphorylated Cbfa1 recruiting other proteins such as
co-activators, modifiers of the nucleosome and the general
transcription factors. In another project, we are investigating
the genes whereby PTH induces anabolic effects on bone.
We have found 125 genes and 30 ESTs are regulated by PTH.
Several of these are being pursued including growth factors
and cytokines. In a third project we have shown that extracellular
concentrations of collagenase-3 are regulated by the existence
of a specific receptor which binds the enzyme. Subsequent
internalization and degradation of collagenase-3 require
transfer to the endocytotic receptor, low-density lipoprotein
receptor-related protein-1. We have recently purified the
specific receptor as a 170 kDa protein. We are now further
characterizing the collagenase-3 removal process in osteoblasts.
Recent publications:
Raggatt, L.J.,
Qin, L., Tamasi, J., Jefcoat , S.C. , Jr., Liew, F.Y., Bevelock,
L., Shimizu , E., Selvamurugan, N., Feyen, J.H.M., and Partridge,
N.C. IL-18 is regulated by parathyroid hormone and is required
for its bone-anabolic actions. J. Biol. Chem., in press,
2008.
Lee, M., Shimizu
, E., Krane, S.M., and Partridge, N.C. Bone Proteinases.
In "Principles of Bone Biology” (eds. J.P. Bilizekian
and L.G. Raisz) Academic Press, San Diego , 3 rd edition,
in press, 2008.
Li, X., Qin, L.,
and Partridge. N.C. In vivo PTH treatments and RNA isolation/analysis.
Invited chapter in "Osteoporosis-Methods in Molecular
Medicine" (Westendorf, ed.), in press, 2008.
Qin, L., and Partridge,
N.C. Gene expression profiles and transcription factors
involved in parathyroid hormone signaling in osteoblastic
cells. Invited chapter in "DNA Microarray Analysis
of Endocrine Cells in Health and Disease " (Handwerger
and Aronow, eds.) in press, 2008.
Bergenstock, M.K.,
and Partridge, N.C. Parathyroid hormone stimulation of noncanonical
Wnt signaling in bone. Ann. N.Y. Acad. 1116, 354-359, 2007.
Shimizu , E.,
Selvamurugan, N., Westendorf, J.J., and Partridge, N.C.
Parathyroid hormone regulates histone deacetylases in osteoblasts.
Ann. N.Y. Acad. 1116, 349-353, 2007.
Li, X., Qin, L.,
Bergenstock, M., Bevelock, L.M., Novack, D.V. and Partridge,
N.C. Parathyroid hormone stimulates osteoblastic expression
of MCP-1 to recruit and increase the fusion of pre/osteoclasts.J.
Biol. Chem., 282, 33098-33106, 2007.
Li., X., Liu,
H., Qin, L., Tamasi, J., Bergenstock, M., Shapses, S., Feyen,
J.H.M., Notterman, D.A., and Partridge, N.C. Determination
of parathyroid hormone's dual effects on skeletal gene expression
in vivo by microarray and network analysis. J. Biol. Chem.,282,
33086-33097, 2007.
Zhu, J., Jia,
X., Xiao, G., Kang, Y., Partridge, N.C., and Qin, L. EGF-like
ligands stimulate osteoclastogenesis by regulating expression
of osteoclast regulatory factors by osteoblasts: implications
for osteolytic bone metastases. J. Biol. Chem., 282, 26656-26664,
2007.
Selvamurugan,
N., Kwok, S., Jefcoat, Jr., S.C., Vasilov, A. and Partridge,
N.C. Effects of BMP-2 and pulsed electromagnetic field (PEMF)
on rat primary osteoblastic cell proliferation and gene
expression. J. Ortho. Res., 25 , 1213-1220, 2007.
Selvamurugan,
N., Jefcoat, Jr., S.C., Kwok, S., Yang, Y., Kowalewski,
R., Tamasi, J.A. and Partridge, N.C. Overexpression of Runx2
directed by the matrix metalloproteinase-13 promoter containing
the AP-1 and Runx/RD/Cbfa sites alters bone remodeling in
vivo. J. Cell. Biochem., 99 , 545-557, 2006.
Raggatt, L.J.,
Jefcoat , S.C. , Jr., Choudhury, I. , Williams, S., Tiku,
M. and Partridge, N.C. Matrix metalloproteinase-13 influences
ERK signalling in articular rabbit chondrocytes. Osteoarthritis
and Cartilage, 14 , 680-689, 2006.
Partridge, N.C.,
Li, X. and Qin, L. Understanding parathyroid hormone action.
Ann. NY Acad. Sci., 1068 , 187-193, 2006.
Qin, L. and Partridge,
N.C. The stimulation of amphiregulin expression in osteoblastic
cells by parathyroid hormone requires protein kinase A and
the cAMP response element-binding protein signaling pathway.
J. Cell. Biochem., 96, 632-640 2005.
Kwok, S., Qin,
L., Partridge, N.C. and Selvamurugan, N. Parathyroid hormone
stimulation and PKA signaling of latent transforming growth
factor-ß binding protein-1 (LTBP-1) mRNA expression
in osteoblastic cells. J. Cell. Biochem., 95, 1002-1011,
2005.
Boumah, C., Selvamurugan,
N. and Partridge, N.C. Transcription in the osteoblast:
regulatory mechanisms utilized by parathyroid hormone and
transforming growth factor-beta. Progress in Nucleic Acid
Research and Molecular Biology 80, 287-321, 2005.
Qin, L., Tamasi,
J., Raggatt, L.J., Li, X., Feyen, J.H.M., Lee, D.C., DiCicco-Bloom,
E. and Partridge, N.C. Amphiregulin is a novel growth factor
involved in normal bone development and in the cellular
response to parathyroid hormone stimulation. J. Biol. Chem.,
280 , 3974-3981, 2005.
Qin, L., Xin,
L., Ko, J.-K. and Partridge, N.C. Parathyroid hormone uses
multiple mechanisms to arrest the cell cycle progression
of osteoblastic cells from G1 to S phase. J. Biol. Chem.,
280 , 3104-3111, 2005.
Selvamurugan,
N., Kwok, S. and Partridge, N.C. Smad3 interacts with JunB
and Cbfa1/Runx2 for transforming growth factor-ß1-stimulated
collagenase-3 expression in human breast cancer cells. J.
Biol. Chem., 279 , 27764-27773, 2004.
Shah, R., Alvarez,
M., Jones, D.R., Torrungruang, K., Watt, A.J., Selvamurugan,
N., Partridge, N.C., Quinn, C.O., Pavalko, F.M., Rhodes,
S.J. and Bidwell, J.P. Nmp4/CIZ regulation of matrix
metalloproteinase 13 (MMP-13) response to parathyroid
hormone in osteoblasts. Am. J. Physiol., 287 , E289-E296,
2004.
Selvamurugan,
N., Kwok, S., Tamara, A., Reiss, M. and Partridge, N.C.
Transforming growth factor-ß1 regulation of collagenase-3
expression in osteoblastic cells by a cross-talk between
Smad and MAPK signaling pathways and their components, Smad2
and Runx2. J. Biol. Chem., 279 , 19327-19334, 2004.
Qin, L., Raggatt,
L.J. and Partridge, N.C. Parathyroid hormone: a double-edged
sword for bone metabolism. Trends in Endocrinology and Metabolism,
15 , 60-65, 2004.
Qiu, P., Qin,
L., Sorrentino, R.P., Greene, J.R., Partridge, N.C. and
Wang, L. Comparative promoter analysis and its application
in analysis of PTH-regulated gene expression. J. Mol. Biol.,
328 , 1327-1336, 2003.
Qin, L., Qiu,
P., Wang, L., Li, X., Swarthout, J.T., Soteropoulos P.,
Tolias, P. and Partridge, N.C. Gene expression profiles
and transcription factors involved in parathyroid hormone
signaling in osteoblasts revealed by microarray and bioinformatics.
J. Biol. Chem., 278, 19723-19731, 2003.
Walling, H.W.,
Raggatt, L.J., Irvine, D.W., Barmina, O.Y., Toledano, J.E.,
Goldring, M.B., Hruska, K.A., Adkisson, H.D., Burdge, R.E.,
Gatt, C.J., Jr., Harwood, D.A. and Partridge, N.C. Impairment
of the collagenase-3 endocytotic receptor system in cells
from patients with osteoarthritis. Osteoarthritis and Cartilage,
11, 854-863, 2003.
Doggett, T.A.,
Swarthout, J.T., Jefcoat , S.C. , Wilhelm, D., Dieckman,
A., Angel, P. and Partridge, N.C. Parathyroid hormone inhibits
c-Jun N-terminal kinase activity in rat osteoblastic cells
by a protein kinase A dependent pathway. Endocrinology,
143 , 1880-1888, 2002.
Tyson, D.R., Swarthout,
J.T., Jefcoat, S.C. and Partridge, N.C. Parathyroid hormone
induction of transcriptional activity of the cAMP response
element binding protein requires the serine 129 site and
glycogen synthase kinase-3 activity but not casein kinase
II sites. Endocrinology, 143 , 674-682, 2002.
Swarthout, J.T.,
D'Alonzo, R.C., Selvamurugan, N. and Partridge, N.C. PTH
dependent signalling pathways regulating genes in bone cells.
Gene, 282 , 1-17, 2002.
D'Alonzo, R.C.,
Selvamurugan, N., Karsenty, G., and Partridge, N.C. Physical
interaction of the activator protein-1 factors, c-Fos and
c-Jun, with Cbfa1 for collagenase-3 promoter activation.
J. Biol. Chem., 277 , 816-822, 2002.
D'Alonzo, R.C.,
Selvamurugan, N., Krane, S.M. and Partridge, N.C. Bone proteinases.
In "Principles of Bone Biology" (eds. J.P. Bilizekian,
L.G. Raisz and G.A. Rodan) Academic Press, San Diego, 2
nd edition, pp. 251-264, 2002.
Swarthout, J.T.,
Tyson, D.R., Jefcoat, S.C. and Partridge, N.C. Induction
of transcriptional activity of the cAMP response element
binding protein by parathyroid hormone and epidermal growth
factor in osteoblastic cells. J. Bone Min. Res., 17, 1401-1407,
2002.
D’Alonzo,
R.C., Kowalski, A.J., Denhardt, D.T., Nickols, G.A., and
Partridge, N.C. Regulation of collagenase-3 and osteocalcin
gene expression by collagen and osteopontin in differentiating
MC3T3-E1 cells. J. Biol. Chem., 277, 24788-24798, 2002.
Raggatt, L.J.
and Partridge, N.C. HMG-CoA reductase inhibitors as immunomodulators:
Potential use in transplant rejection. Drugs, 62, 2185-2191,
2002.
Selvamurugan,
N., Fung, Z. and Partridge, N.C. Transcriptional activation
of collagenase-3 by transforming growth factor-?1 is via
MAPK and Smad pathways in human breast cancer cells. FEBS
Lett. 532, 31-35, 2002.
Barmina, O.Y.,
Walling, H.W., Fiacco, G.J., Lopez-Otin, C., Jeffrey, J.J.
and Partridge, N.C. Collagenase-3 binds to a specific receptor
and requires the LDL-receptor related protein for internalization.
J. Biol. Chem., 274, 30087-30093, 1999.
Selvamurugan,
N., Pulumati, M.R., Tyson, D.R. and Partridge, N.C. Parathyroid
hormone regulation of the rat collagenase-3 promoter by
protein kinase A-dependent transactivation of core binding
factor A1. J. Biol. Chem., 275, 5037-5042, 2000.
Tuckermann, J.P.,
Pittois, K., Partridge, N.C., Merregaert, J. and Angel,
P. MMP-13 and Itm2a are marker genes of chondrogenic/osteoblastic
cells in bone formation: Sequential temporal and spatial
expression of Itm2a, alkaline phosphatase, MMP-13 and osteocalcin
in the mouse. J. Bone Min. Res., 15, 1257-1265, 2000.
Winchester, S.K.,
Selvamurugan, N., D'Alonzo, R.C. and Partridge, N.C. Developmental
regulation of collagenase-3 mRNA in normal, differentiating
osteoblasts through the activator protein-1 and the runt
domain binding sites. J. Biol. Chem., 275, 23310-23318,
2000.
Partridge, N.C.,
Fiacco, G.J., Walling, H.W., Barmina, O.Y., Jeffrey, J.J.,
and Ruh, M.F. Effects of dioxin and estrogen on collagenase-3
in osteoblasts. Arch. Biochem. Biophys., 382, 182-188, 2000.
Swarthout, J.T.,
Doggett, T.A., Lemker, J.L. and Partridge, N.C. Stimulation
of extracellular signal-regulated kinases and proliferation
in rat osteoblastic cells by parathyroid hormone is protein
kinase C dependent. J. Biol. Chem., 276, 7586-7592, 2001.
Staff:
Emi Shimizu ,
Ph.D., Postdoctoral Fellow
Marika Bergenstock,
Graduate Student
Minkyong Lee,
Graduate Student
Joseph Tamasi,
Graduate Student
Anatolive Vasilov,
M.D., Research Teaching Specialist IV
Volodymyr Khlystov,
PT lab tech
Paola Duran, Undergraduate
Student
Graduate Program
Membership:
Physiology and
Integrative Biology
Cellular and Molecular
Pharmacology
Molecular Genetics
and Microbiology
Microbiology and
Molecular Genetics (joint w/Rutgers)
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