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(LRF) in the Transcriptional Control of Osteoclast Development Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development Kaori Tsuji-Takechia,b,c, Takako Negishi-Kogaa,b,d, Eriko Sumiyaa,b,d, Akiko Kukitae, Shigeaki Katof, Takahiro Maedag,1, Pier Paolo Pandolfig, Keiji Moriyamab,c, and Hiroshi Takayanagia,b,d,h,2 aDepartment of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan; bGlobal Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Bunkyo-ku, Tokyo 113-8549, Japan; cDepartment of Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan; dTakayanagi Osteonetwork Project, Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Bunkyo-ku, Tokyo 113-8549, Japan; eDepartment of Microbiology, Faculty of Medicine, Saga University, Saga-shi, Saga 849-8501, Japan; fInstitute of Molecular and Cellular Biosciences, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; gCancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and hCentre for Orthopaedic Research, School of Surgery, University of Western Australia, Nedlands, WA 6009, Australia Edited by Laurie H. Glimcher, Weill Cornell Medical College, New York, NY, and approved January 4, 2012 (received for review October 6, 2011) Cell fate determination is tightly regulated by transcriptional activa- oncogenesis of T- and B-cell lymphoma, prostate, breast, non– tors and repressors. Leukemia/lymphoma-related factor (LRF; encoded small-cell lung, and ovarian cancers (14–18). LRF exerts its onco- by Zbtb7a), known as a POK (POZ/BTB and Krüppel) family transcrip- genic effect by suppressing the expression of the tumor suppressor tional repressor, is induced during the development of bone-resorbing genes Arf and Rb (14, 19). LRF is implicated not only in onco- osteoclasts, but the physiological significance of LRF in bone metab- genesis, but also in diverse biological processes such as cell survival olism and the molecular mechanisms underlying the transcriptional and lineage fate decisions in hematopoietic cells (20–22). regulation of osteoclastogenesis by LRF have not been elucidated. In the skeletal system, osteoclast-derived zinc finger (OCZF), Here we show that LRF negatively regulates osteoclast differentiation a rat homolog of LRF, was originally identified as an osteoclast- by repressing nuclear factor of activated T cells c1 (NFATc1) induction specific protein in a screening performed with monoclonal in the early phase of osteoclast development, while positively regu- antibodies (23). Recently, mice overexpressing LRF in osteo- lating osteoclast-specific genes by functioning as a coactivator of clasts were shown to exhibit an osteoporotic phenotype due to NFATc1 in the bone resorption phase. The stage-specificdistinctfunc- the increased number of osteoclasts (24). However, the physio- tions of LRF were demonstrated in two lines of conditional knockout logical function of LRF in bone remodeling has not been dem- mice in which LRF was deleted in the early or late phase of osteoclast onstrated, because global deletion of LRF results in embryonic fi development. Thus, this study shows that LRF plays stage-speci c lethality (14). Thus, we investigated the function of LRF in distinct roles in osteoclast differentiation, exemplifying the delicate osteoclastogenesis by disrupting Zbtb7a at the early and late transcriptional regulation at work in lineage commitment. stages of osteoclast differentiation using Mx1- and Ctsk-Cre mice, MEDICAL SCIENCES respectively. The distinct phenotypes of the two conditional steoclasts are responsible for both physiological and patho- knockout mice revealed that LRF plays certain stage-specific Ological bone resorption, and an accurate understanding of the roles in the transcriptional program of osteoclast development. molecular mechanisms of osteoclast differentiation is thus crucially important for the development of therapeutic strategies against Results bone and joint diseases (1–3). Receptor activator of nuclear factor- Physiological and Ectopic Expression of LRF During Osteoclastogenesis. κB (NF-κB) ligand (RANKL) is an essential cytokine that induces We examined the expression and localization of the LRF protein the differentiation of monocyte/macrophage lineage cells into during osteoclastogenesis. LRF was only slightly expressed in os- osteoclasts in the presence of macrophage colony-stimulating fac- teoclast precursor cells, but was markedly induced in bone marrow- tor (M-CSF) (2, 3). RANKL promotes osteoclastogenesis through derived monocyte/macrophage precursor cells (BMMs) stimulated the induction and autoamplification of the key transcription factor with RANKL (Fig. S1A). LRF accumulated in the nuclei as BMMs nuclear factor of activated T cells c1 (NFATc1), which transcrip- underwent differentiation into osteoclasts (Fig. S1B), suggesting fi tionally regulates most of the osteoclast-speci c genes required for that it has a role in gene regulation. To examine the effect of the Ctsk the bone resorbing activity, including (encoding cathepsin K), ectopic expression of LRF at the early and late stages of osteoclast Mmp-9 Clcn7 – ,and (encoding chloride channel 7) (3 6). The auto- differentiation, we infected BMMs at distinct time points with fi ampli cation of NFATc1 is a hallmark event in the early phase of aretroviralvectorcarryingtheZbtb7a gene (pMX-LRF-IRES- osteoclast development, in which NFATc1 is preferentially re- EGFP). When BMMs were infected with the LRF-expressing fi cruited to its own promoter, thus enabling the autoampli cation of retrovirus, the formation of tartrate-resistant acid phosphatase fi fi expression (3, 7, 8). To achieve ef cient NFATc1 autoampli ca- (TRAP)-positive multinucleated cells (MNCs) was significantly tion, transcription factors such as NF-κB and c-Fos are required. Osteoclast differentiation is negatively regulated by the transcrip- tion factors IFN regulatory factor-8 (IRF-8), v-maf muscu- fi Author contributions: K.T.-T., T.N.-K., and H.T. designed research; K.T.-T. performed re- loaponeurotic brosarcoma oncogene family protein B (MafB), search; A.K., S.K., T.M., and P.P.P. contributed new reagents/analytic tools; K.T.-T., T.N.-K., and B-cell lymphoma 6 (Bcl-6), mainly through the inhibition of E.S., and K.M. analyzed data; and H.T. wrote the paper. NFATc1 activity and expression (9–11). Thus, NFATc1 expression The authors declare no conflict of interest. is controlled by a delicate balance between positive and negative This article is a PNAS Direct Submission. transcriptional regulators during osteoclastogenesis. 1Present address: Hematology Division, Brigham and Women’s Hospital, Harvard Medical Leukemia/lymphoma-related factor (LRF, also called Pokemon: School, 1 Blackfan Circle, Boston, MA 02115. POK erythroid myeloid ontogenic factor), which is encoded by the 2To whom correspondence should be addressed. E-mail: [email protected]. Zbtb7a Krüppel gene, is a member of the POK (POZ/BTB and ) This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. family of transcriptional repressors (12, 13). LRF is involved in the 1073/pnas.1116042109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1116042109 PNAS | February 14, 2012 | vol. 109 | no. 7 | 2561–2566 Downloaded by guest on October 1, 2021 fl A pMX-IRES pMX-LRF the mature osteoclasts was not in uenced by this ectopic expres- -EGFP -IRES-EGFP sion of LRF in the late stage of osteoclast development (Fig. 1B pMX-IRES-EGFP and Fig. S2). These results suggest that LRF negatively regulates pMX-LRF-IRES-EGFP osteoclast differentiation at the early but not the late stage of ) 2 osteoclastogenesis. It has been reported (24), however, that over- EGFP + Ctsk 450 expression of LRF under the promoter results in a prolonged survival of osteoclasts. These inconsistent in vitro results suggest TRAP + 300 that in vivo loss-of-function studies will be required for a clear understanding of the physiological function of LRF. 150 EGFP ** TRAP Differentiation Stage-Specific Disruption of LRF. To explore the MNC number (/cm MNC 0 physiological role of LRF in the osteoclast lineage, we inves- tigated LRF conditional knockout mice. Because LRF exerted stage-specific effects in vitro, we generated two types of LRF Flox/FloxMx1cre+ B pMX-IRES pMX-LRF conditional knockout mice, Zbtb7a (20) and -EGFP -IRES-EGFP Flox/− Cre/+ Flox/Flox pMX-IRES-EGFP Zbtb7a Ctsk mice, by crossing Zbtb7a with Mx1- Flox/− pMX-LRF-IRES-EGFP Cre transgenic mice and Zbtb7a with Ctsk-Cre knock-in Cre/+ Flox/FloxMx1cre+ ) (Ctsk ) mice, respectively. In the Zbtb7a mice, 2 EGFP + the Zbtb7a gene is deleted upon polyinosinic-polycytidylic acid 450 (poly I:C) treatment in various cell types, including immature he- TRAP matopoietic cells, which allowed us to examine the effect of LRF + 300 depletion at the very early stage of osteoclast development. In fact, 150 the expression of both the LRF protein and mRNA was un- EGFP TRAP detectable at the stage of osteoclast precursor cells (time 0) in the MNC number (/cm MNC 0 Flox/FloxMx1cre+ Flox/− Cre/+ Zbtb7a cells (Fig. 1C). In the Zbtb7a Ctsk mice, the Zbtb7a gene was deleted at the later stage of osteoclast Zbtb7aFlox Flox lineage cells
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