title: IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass.
abstract: The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4(+) T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23-induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19(-/-) mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19(-/-) mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides.
authors.affiliation: Discovery Research, Merck Research Laboratories, Palo Alto, CA 94304, USA. iannis.adamopoulos@ucdmc.ucdavis.edu
authors.forename: Iannis E
authors.initials: IE
authors.lastname: Adamopoulos
authors.forename: Marlowe
authors.initials: M
authors.lastname: Tessmer
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chao
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Adda
authors.forename: Dan
authors.initials: D
authors.lastname: Gorman
authors.forename: Mary
authors.initials: M
authors.lastname: Petro
authors.forename: Chuan-Chu
authors.initials: CC
authors.lastname: Chou
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.forename: Drake
authors.initials: D
authors.lastname: Laface
authors.forename: Edward P
authors.initials: EP
authors.lastname: Bowman
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D001862:Bone Resorption / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016466:CHO Cells; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002908:Chronic Disease; D006224:Cricetinae; D003412:Cricetulus; D018105:DNA, Kinetoplast / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D053760:Interleukin-23 Subunit p19 / Q000172:deficiency / Q000302:isolation & purification / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000276:immunology* / Q000473:pathology*; D012720:Severity of Illness Index; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018105:DNA, Kinetoplast; D053760:Interleukin-23 Subunit p19