title: STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis.
abstract: Among the diverse cytokines involved in osteoclast differentiation, interleukin (IL)-3 inhibits RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. Here we demonstrate that the activation of signal transducers and activators of transcription 5 (STAT5) by IL-3 inhibits RANKL-induced osteoclastogenesis through the induction of the expression of Id genes. We found that STAT5 overexpression inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate the expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting a key role of STAT5 in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated the expression of Id1 and Id2, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Importantly, microcomputed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in the STAT5 conditional knockout mice than in the wild-type mice after RANKL injection. Taken together, our findings indicate that STAT5 contributes to the remarkable IL-3-mediated inhibition of RANKL-induced osteoclastogenesis by activating Id genes and their associated pathways.
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.|Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Semun
authors.initials: S
authors.lastname: Seong
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Jung Ha
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Kabsun
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Inyoung
authors.initials: I
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.|Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Jeong
authors.affiliation: Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Nam
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20814, USA.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.affiliation: Department of Pharmacology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.|Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis / Q000235:genetics; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000235:genetics; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497455:Idb1 protein, mouse; C497452:Idb2 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D007377:Interleukin-3; D053245:RANK Ligand; D050799:STAT5 Transcription Factor; C505689:Tnfsf11 protein, mouse