Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects

Because JunB is an essential gene for placentation, it was conditionally deleted in the embryo proper. JunB Δ/Δ mice are born viable, but develop severe low turnover osteopenia caused by apparent cell-autonomous osteoblast and osteoclast defects before a chronic myeloid leukemia-like disease. Although JunB was reported to be a negative regulator of cell proliferation, junB Δ/Δ osteoclast precursors and osteoblasts show reduced proliferation along with a differentiation defect in vivo and in vitro. Mutant osteoblasts express elevated p16INK4a levels, but exhibit decreased cyclin D1 and cyclin A expression. Runx2 is transiently increased during osteoblast differentiation in vitro, whereas mature osteoblast markers such as osteocalcin and bone sialoprotein are strongly reduced. To support a cell-autonomous function of JunB in osteoclasts, junB was inactivated specifically in the macrophage–osteoclast lineage. Mutant mice develop an osteopetrosis-like phenotype with increased bone mass and reduced numbers of osteoclasts. Thus, these data reveal a novel function of JunB as a positive regulator controlling primarily osteoblast as well as osteoclast activity.

[1]  W. Reith,et al.  Conditional gene targeting in macrophages and granulocytes using LysMcre mice , 1999, Transgenic Research.

[2]  P. Angel,et al.  Defective endochondral ossification in mice with strongly compromised expression of JunB , 2003, Journal of Cell Science.

[3]  E. Wagner,et al.  AP-1: a double-edged sword in tumorigenesis , 2003, Nature Reviews Cancer.

[4]  E. Wagner,et al.  Impaired intervertebral disc formation in the absence of Jun , 2003, Development.

[5]  Hiroshi Takayanagi,et al.  Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. , 2002, Developmental cell.

[6]  E. Wagner,et al.  JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms , 2002, Journal of Cell Science.

[7]  A. Kolbus,et al.  Cell Cycle Promoting Activity of JunB through Cyclin A Activation* , 2002, The Journal of Biological Chemistry.

[8]  M. Karin,et al.  AP-1 as a regulator of cell life and death , 2002, Nature Cell Biology.

[9]  E. Wagner,et al.  Reaching a genetic and molecular understanding of skeletal development. , 2002, Developmental cell.

[10]  E. Wagner,et al.  JunB can substitute for Jun in mouse development and cell proliferation , 2002, Nature Genetics.

[11]  P. Plinkert,et al.  The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. , 2001, Experimental cell research.

[12]  N. Kanatani,et al.  Overexpression of Cbfa1 in osteoblasts inhibits osteoblast maturation and causes osteopenia with multiple fractures , 2001, The Journal of cell biology.

[13]  R. Baron,et al.  Carbonic anhydrase II is an AP‐1 target gene in osteoclasts , 2001, Journal of cellular physiology.

[14]  E. Wagner,et al.  AP-1 in mouse development and tumorigenesis , 2001, Oncogene.

[15]  E. Wagner,et al.  Chronic Myeloid Leukemia with Increased Granulocyte Progenitors in Mice Lacking JunB Expression in the Myeloid Lineage , 2001, Cell.

[16]  R. Baron,et al.  Progressive increase in bone mass and development of odontomas in aging osteopetrotic c-src-deficient mice. , 2000, Bone.

[17]  E. Wagner,et al.  Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1 , 2000, Nature Medicine.

[18]  M. Kelz,et al.  Overexpression of ΔFosB transcription factor(s) increases bone formation and inhibits adipogenesis , 2000, Nature Medicine.

[19]  M. Wani,et al.  A role for TGFbeta(1) in osteoclast differentiation and survival. , 2000, Journal of cell science.

[20]  E. Wagner,et al.  JunB suppresses cell proliferation by transcriptional activation of p16INK4a expression , 2000, The EMBO journal.

[21]  E. Bossy‐Wetzel,et al.  Cell cycle‐dependent variations in c‐Jun and JunB phosphorylation: a role in the control of cyclin D1 expression , 2000, The EMBO journal.

[22]  Philippe Soriano,et al.  Epiblast‐restricted Cre expression in MORE mice: A tool to distinguish embryonic vs. extra‐embryonic gene function , 2000, Genesis.

[23]  E. Wagner,et al.  Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation , 2000, Nature Genetics.

[24]  J. Weitzman,et al.  Targeted disruption of the murine junD gene results in multiple defects in male reproductive function. , 2000, Development.

[25]  J. Aubin,et al.  Kinetics of osteoprogenitor proliferation and osteoblast differentiation in vitro , 1999, Journal of cellular biochemistry.

[26]  Frank Hilberg,et al.  Functions of c-Jun in Liver and Heart Development , 1999, The Journal of cell biology.

[27]  G. Karsenty,et al.  A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. , 1999, Genes & development.

[28]  E. Wagner,et al.  JunB is essential for mammalian placentation , 1999, The EMBO journal.

[29]  A. Lassar,et al.  Sonic hedgehog promotes somitic chondrogenesis by altering the cellular response to BMP signaling. , 1999, Genes & development.

[30]  R. Johnson,et al.  c‐Jun regulates cell cycle progression and apoptosis by distinct mechanisms , 1999, The EMBO journal.

[31]  R. Baron,et al.  Printed in U.S.A. Copyright © 1999 by The Endocrine Society Rescue of the Skeletal Phenotype of Vitamin D Receptor- Ablated Mice in the Setting of Normal Mineral Ion , 2022 .

[32]  B. Frenkel,et al.  AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation. , 1999, Endocrinology.

[33]  R. Baron,et al.  Dissociation between bone resorption and bone formation in osteopenic transgenic mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Makoto Sato,et al.  Targeted Disruption of Cbfa1 Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts , 1997, Cell.

[35]  G. Karsenty,et al.  Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation , 1997, Cell.

[36]  L. Freedman,et al.  AP-1 regulation of the rat bone sialoprotein gene transcription is mediated through a TPA response element within a glucocorticoid response unit in the gene promoter. , 1996, Matrix biology : journal of the International Society for Matrix Biology.

[37]  E. Wagner,et al.  The human ubiquitin C promoter directs high ubiquitous expression of transgenes in mice. , 1996, Nucleic acids research.

[38]  G. Stein,et al.  Selective expression of fos- and jun-related genes during osteoblast proliferation and differentiation. , 1995, Experimental cell research.

[39]  E. Wagner,et al.  c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. , 1994, Science.

[40]  E. Wagner,et al.  Osteoblasts are target cells for transformation in c-fos transgenic mice , 1993, The Journal of cell biology.

[41]  M. Karin,et al.  Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun , 1989, Cell.

[42]  M. Drezner,et al.  Bone histomorphometry: Standardization of nomenclature, symbols, and units: Report of the asbmr histomorphometry nomenclature committee , 1987, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[43]  M. Wani,et al.  A role for TGF β 1 in osteoclast differentiation and survival , 2022 .