title: Progranulin and a five transmembrane domain-containing receptor-like gene are the key components in receptor activator of nuclear factor κB (RANK)-dependent formation of multinucleated osteoclasts.
abstract: Homeostatic bone remodeling is vital to maintain healthy bone tissue. Although the receptor activator of nuclear factor κB ligand (RANKL)/RANK axis is considered the master regulator of osteoclastogenesis, the underlying mechanisms including cell fusion remain incompletely defined. Here, we introduce a new axis in the formation of multinucleated cells via RANK signaling: the progranulin (PGRN)/PIRO (PGRN-induced receptor-like gene during osteoclastogenesis) axis. When mouse bone marrow-derived macrophages were stimulated with PGRN in the presence of RANKL, explosive OC formation was observed. PGRN knockdown experiments suggested that endogenous PGRN is an essential component of the RANKL/RANK axis. Our efforts for identifying genes that are induced by PGRN unveiled a remarkably induced (20-fold) gene named PIRO. Substantial PGRN and PIRO expression was detected after 2 and 3 days, respectively, suggesting that their sequential induction. PIRO was predicted to be a five transmembrane domain-containing receptor-like molecule. The tissue distribution of PGRN and PIRO mRNA expression suggested that bone marrow cells are the most suitable niche. Mouse and human PIRO are part of a multigene family. Knockdown experiments suggested that PIRO is a direct target for the formation of multinucleated cells by PGRN. PGRN levels were also substantially higher in ovariectomized mice than in sham control mice. These observations suggest that PGRN and PIRO form a new regulatory axis in osteoclastogenesis that is included in RANK signaling in cell fusion and OC resorption of osteoclastogenesis, which may offer a novel therapeutic modality for osteoporosis and other bone-associated diseases.
authors.affiliation: From the Imaging Science-based Lung and Bone Diseases Research Center, the Departments of Anatomy and the BK21plus Program, Graduate School.
authors.forename: Jaemin
authors.initials: J
authors.lastname: Oh
authors.affiliation: From the Imaging Science-based Lung and Bone Diseases Research Center.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: the Institute for Bio-Medical Convergence, Catholic Kwandong University and Innovative Cell & Gene Therapy Center, International St. Mary's Hospital, Incheon 404-834, Korea, and.
authors.forename: Han-Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: the Departments of Anatomy and.
authors.forename: Justin Cheesung
authors.initials: JC
authors.lastname: Oh
authors.affiliation: the Departments of Anatomy and the BK21plus Program, Graduate School.
authors.forename: Yoon-Hee
authors.initials: YH
authors.lastname: Cheon
authors.affiliation: the Department of Neurosurgery, and.
authors.forename: Jongtae
authors.initials: J
authors.lastname: Park
authors.affiliation: From the Imaging Science-based Lung and Bone Diseases Research Center, Radiology, School of Medicine.
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.affiliation: From the Imaging Science-based Lung and Bone Diseases Research Center, the Division of Rheumatology, Department of Internal Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Korea, ckhlms@wku.ac.kr.
authors.forename: Myeung Su
authors.initials: MS
authors.lastname: Lee
authors.affiliation: the Departments of Anatomy and OsteoNeuroGen, Bundang, Kyunggi-Do 461-871, Korea byung4jc@gmail.com.
authors.forename: Byung-Soo
authors.initials: BS
authors.lastname: Youn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption; D019295:Computational Biology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D000077155:Granulins; D006801:Humans; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D000077153:Progranulins; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C492314:GRN protein, human; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D034741:RNA, Small Interfering; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505687:Tnfrsf11a protein, mouse
keywords: Bone; Cell Fusion; Cytokine; Genomics; Osteoclast; Osteoporosis; Receptor