Genomes and Genes
Coloney Stimulating Factor 1 regulation and role in bone
Principal Investigator: KARL LEONARD INSOGNA
Abstract: Colony stimulating factor-1 (CSF1) is required for osteoclast progenitor proliferation and differentiation, the latter dependent in part on activation of the transcription factor, Mitf. Recent evidence indicates an important role for CSF1 in states of accelerated bone loss including estrogen-deficiency, inflammatory arthritis and malignancy-induced bone resorption. Alternative splicing of the CSF-1 gene results in production of soluble (sCSF1) and cell-surface (mCSF1) isoforms. We have found that restricted over-expression of either mCSF1 or sCSF1 in osteoblasts causes bone loss in vivo. We then crossed op/op mice with these transgenic mice to create animals with selective over expression of each isoform in bone, in the absence of endogenous CSF1. Interestingly, while mCSF1 completely rescued the osteopetrotic phenotype of the op/p mouse, the bone density in sCSF1-op/op mice did not completely normalize. Surprisingly, following ovariectomy, sCSF-op/op mice lost significantly more bone than the mCSF1-op/op mice, suggesting that sCSF1 plays a more important role in mediating estrogen-deficiency bone loss. Consistent with this finding, isoform-specific real-time PCR documented increased expression of sCSF1 in the bone RNA of ovariectomized mice while levels of mCSF1 did not change. We are now beginning studies in mCSF1 and sCSF1 knock out mice. Preliminary results from mCSF1 knock out mice indicate that they have increased bone mass and reduced number of osteoclasts. To identify CSF-1 target genes in osteoclasts, we have used a gene profiling approach and found 7 genes induced by CSF1 in an Mitf-dependent manner. To pursue these findings and to test the hypothesis that the two CSF1 isoforms serve non-redundant roles in bone, we will determine if isoform-selective deletion of CSF1 alters the skeletal response to resorptive stimuli including ovariectomy and continuous PTH infusion and conversely, if the absence of each isoform differentially affects the anabolic response to PTH. We will determine the isoform of CSF1 preferentially up regulated in osteoblasts following estrogen withdrawal and assay the importance of this change in vivo by ovariectomizing mice with isoform-selective deletion of each CSF1 isoform in osteoblasts. We will determine the effect of sCSF1 and mCSF1 on the extent and time course of induction of 2 the 7 candidate genes identified in the CSFl-"Mitf pathway, one, Jun-dimerization protein-2, is required for osteoclastogenesis and one, pi 10a, is known to have a role in differentiated osteoclast function. We will use these two genes as probes to further test the hypothesis that the two CSF1 isoforms act differently in osteoclasts. We will also use EMSA and mutational promoter analyses to determine the role of Mitf in CSF1 isoform-induced transcription of these two genes. In the aggregate, these studies will clarify the roles of the two CSF1 isoforms in bone as well as begin to define CSF-1 regulated genes in osteoclasts. Since CSF1 is emerging as an important target for drug discovery in treating low bone mass, these data will provide critical information that will inform and refine our approach to this target.
Funding Period: ----------------1992 - ---------------2011-
more information: NIH RePORT
- The cell-surface isoform of colony stimulating factor 1 (CSF1) restores but does not completely normalize fecundity in CSF1-deficient miceShira Ovadia
Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA
Biol Reprod 74:331-6. 2006..These data are consistent with the conclusion that mCSF1, when shed from the cell surface, can support reproduction and that high uterine tissue levels of CSF1 may not be required for mouse reproduction...
- LIM kinase 1 deficient mice have reduced bone massTsutomu Kawano
Department of Medicine, Yale School of Medicine, New Haven, CT 06520 8020, USA
Bone 52:70-82. 2013..These data support the hypothesis that LIMK1 is required for normal osteoblast differentiation. In addition, its absence leads to increased cytoskeletal remodeling and bone resorption in osteoclasts...
- The transcription factor T-box 3 regulates colony-stimulating factor 1-dependent Jun dimerization protein 2 expression and plays an important role in osteoclastogenesisChen Yao
From the Department of Internal Medicine
J Biol Chem 289:6775-90. 2014..The downstream signaling cascade from activated c-Fms involves the MEK1/2-ERK1/2 pathway. Tbx3 plays an important role in osteoclastogenesis at least in part by regulating CSF1-dependent expression of JDP2. ..
- Breast cancer-associated gene 3 (BCA3) is a novel Rac1-interacting proteinKuan Ping Yu
Department of Medicine, Yale School of Medicine, New Haven, CT 06520 8020, USA
J Bone Miner Res 22:628-37. 2007..Perinuclear co-localization of BCA3 and Rac1 is observed in CSF-1-treated osteoclasts. Overexpression of BCA3 attenuates CSF-1-induced cell spreading. We conclude that BCA3 regulates CSF-1-dependent Rac activation...
- Colony-stimulating factor-1 increases osteoclast intracellular pH and promotes survival via the electroneutral Na/HCO3 cotransporter NBCn1Patrice Bouyer
Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, POB 208026, New Haven, Connecticut 06520 8026, USA
Endocrinology 148:831-40. 2007..This study provides the first evidence that osteoclasts express a CSF-1-regulated Na/HCO(3) cotransporter, which may play a role in cell survival...
- Effects of glucose-dependent insulinotropic peptide on osteoclast functionQing Zhong
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA
Am J Physiol Endocrinol Metab 292:E543-8. 2007..These data are consistent with the hypothesis that GIP inhibits bone breakdown through a direct effect on osteoclast-resorptive activity and suggest one mechanism for the postprandial reduction in markers of bone breakdown...
- Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in boneBart O Williams
Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
J Bone Miner Res 24:171-8. 2009....
- Dominant role of CD47-thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone diseaseAnjli Kukreja
Section of Hematology, Yale University, New Haven, CT 06510, USA
Blood 114:3413-21. 2009..Disruption of CD47-TSP-1 interactions or preventing the recruitment of DCs to tumors may provide novel approaches to therapy of myeloma bone disease and osteoporosis...
- Targeted overexpression of Dkk1 in osteoblasts reduces bone mass but does not impair the anabolic response to intermittent PTH treatment in miceGang Qing Yao
Section of Comparative Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520 8016, USA
J Bone Miner Metab 29:141-8. 2011..We conclude that overexpression of Dkk1 does not attenuate the anabolic response to PTH in vivo...
- Osteoclasts lacking Rac2 have defective chemotaxis and resorptive activityTakashi Itokowa
Department of Medicine, Yale School of Medicine, 333 Cedar St, TAC S133, New Haven, CT 06520 8020, USA
Calcif Tissue Int 88:75-86. 2011..Finally, Rac2(-/-) osteoclasts showed a marked defect in chemotaxis toward a point source of CSF1, with a dramatic reduction in migratory rate. Together, these findings indicate an important role for Rac2 in mature osteoclasts...
- Targeted overexpression of the two colony-stimulating factor-1 isoforms in osteoblasts differentially affects bone loss in ovariectomized miceGang Qing Yao
Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520 8016, USA
Am J Physiol Endocrinol Metab 296:E714-20. 2009..9%) or in wild-type animals (10.9%). Our findings support the conclusion that sCSF1 and mCSF1 serve nonredundant functions in bone and that sCSF1 may play a role in mediating estrogen-deficiency bone loss...