title: Elevated levels of Interleukin (IL)-33 induce bone pathology but absence of IL-33 does not negatively impact normal bone homeostasis.
abstract: Interleukin (IL)-33 is a member of the IL-1 family. IL-33 effects are mediated through its receptor, ST2 and IL-1RAcP, and its signaling induces the production of a number of pro-inflammatory mediators, including TNFα, IL-1β, IL-6, and IFN-γ. There are conflicting reports on the role of IL-33 in bone homeostasis, with some demonstrating a bone protective role for IL-33 whilst others show that IL-33 induces inflammatory arthritis with concurrent bone destruction. To better clarify the role IL-33 plays in bone biology in vivo, we studied IL-33 KO mice as well as mice in which the cytokine form of IL-33 was overexpressed. Mid-femur cortical bone mineral density (BMD) and bone strength were similar in the IL-33 KO mice compared to WT animals during the first 8months of life. However, in the absence of IL-33, we observed higher BMD in lumbar vertebrae and distal femur in female mice. In contrast, overexpression of IL-33 resulted in a marked and rapid reduction of bone volume, mineral density and strength. Moreover, this was associated with a robust increase in inflammatory cytokines (including IL-6 and IFN-γ), suggesting the bone pathology could be a direct effect of IL-33 or an indirect effect due to the induction of other mediators. Furthermore, the detrimental bone effects were accompanied by increases in osteoclast number and the bone resorption marker of C-terminal telopeptide collagen-I (CTX-I). Together, these results demonstrate that absence of IL-33 has no negative consequences in normal bone homeostasis while high levels of circulating IL-33 contributes to pathological bone loss.
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Okragly
authors.affiliation: Musculoskeletal-Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hamang
authors.affiliation: Musculoskeletal-Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Pena
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Hana E
authors.initials: HE
authors.lastname: Baker
authors.affiliation: Musculoskeletal-Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Bullock
authors.affiliation: Musculoskeletal-Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lucchesi
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Martin
authors.affiliation: Musculoskeletal-Biology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Y Linda
authors.initials: YL
authors.lastname: Ma
authors.affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: benschop_robert@lilly.com.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Benschop
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics / Q000502:physiology*; D001862:Bone Resorption / Q000378:metabolism*; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005269:Femur / Q000502:physiology*; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008159:Lumbar Vertebrae / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology; D010455:Peptides / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D016207:Cytokines; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide
keywords: Aging; Biomechanics; Bone; Genetic deficient mice; IL-33