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Reduced Cortical Bone Mass in Mice with Inactivation of Interleukin-4 and Interleukin-13
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Ortopedi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. (Ortopedi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
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2007 (English)In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 25, no 6, 725-731 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the present study was to study the in vivo role of IL-4 and IL-13 on bone metabolism. The skeletal phenotypes of male and female IL-13-/- (n = 7+7), IL-4-/-IL-13-/- (n = 7+7), and WT (n = 7+7) mice were compared. Analysis was made at 6 weeks of age (juvenile) by pQCT, and at 20 weeks of age (adult) by pQCT, biomechanical testing, and by S-IGF-1 and S-Osteocalcin measurements. The skeletal phenotype was affected only in adult male IL-4-/-IL-13-/- mice. These animals displayed a reduction in cortical bone mineral content (BMC) of both the tibia and the femur, as measured by mid-diaphyseal pQCT scans, compared with WT mice (tibia -8.2%; femur -8.5%; p < 0.01). This reduction in cortical BMC was due to a decreased cross-sectional area as a result of a reduced cortical thickness. The mechanical strength of the cortical bone, tested by three-point-bending at the mid-diaphyseal region of the femurs, demonstrated a significant reduction of displacement at failure (-11.4%), maximal load at failure (-10.6%), and total energy until failure (-29.4%). S-IGF-1 and S-Osteocalcin levels as well as trabecular bone mineral density (tvBMD) were unaffected in adult male IL-4-/-IL-13-/- mice. IL-4-/-IL-13-/- male mice show adult onset reduction of cortical bone mass and strength, indicating that the two anti-inflammatory Th2 cytokines IL-4 and IL-13 are involved in the regulation of bone remodeling.

Place, publisher, year, edition, pages
2007. Vol. 25, no 6, 725-731 p.
Keyword [en]
bone, osteoblasts, interleukin-4, interleukin-13, transgenic
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96656DOI: 10.1002/jor.20361ISI: 000246541300003PubMedID: 17318894OAI: oai:DiVA.org:uu-96656DiVA: diva2:171303
Available from: 2008-01-24 Created: 2008-01-24 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Effects of Interleukin-4 and Interleukin-13 on Bone
Open this publication in new window or tab >>Effects of Interleukin-4 and Interleukin-13 on Bone
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cytokines play important roles in bone metabolism, participating in the complex interplay necessary for normal bone formation and turnover. The aim of the present thesis was to investigate the effects of two anti-inflammatory cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13) on bone.

Influence of pro- and anti-inflammatory cytokines on interleukin-6 (IL-6) formation in cultured human osteoblasts (hOBs) was investigated. IL-4 and IL-13 as well as interleukin-1 (IL-1) and tumour necrosis factor alpha and beta (TNF-α/β) stimulated IL-6 secretion in hOBs. Also, IL-4 and IL-13 synergistically potentiated the effect of IL-1 and TNFs on IL-6 secretion.

Effects of IL-4 and IL-13 on markers of osteoblastic activity in hOBs were investigated. IL-4 and IL-13 induced a dose-dependent increase in the formation of alkaline phosphatase (ALP) and pro-collagen type I carboxy-peptide (PICP) together with enhanced mineralization rate in hOBs. Formation of osteocalcin (OC) was unaffected.

The mechanism behind inhibited proliferation by IL-4 and IL-13 in hOBs was investigated. IL-4 and IL-13 caused a dose-dependent increase in DNA-fragmentation together with escalating Caspase-3 activity in hOBs, reflecting induced apoptosis. Osteoblast apoptosis was also confirmed by TNF-α, dexamethasone and by serum starvation.

The skeletal phenotype of IL-13-/-, IL-4-/-IL-13-/- and WT mice was compared. An altered cortical bone mass was detected in adult male IL-4-/-IL-13-/- mice. They displayed a reduction in cortical bone mineral content (BMC) secondary to reduced cortical thickness. Mechanical strength of the cortical bone was reduced in level with the reduction detected in BMC. Trabecular bone mineral density (tvBMD) was unaffected.

Callus formation in IL-4-/-IL-13-/- and WT male mice was compared. No differences were found concerning radiological healing, biomechanical properties, callus parameters or histology. Heterotopic bone formation in IL-4-/-IL-13-/- and WT mice was compared using DXBM implants. No differences were found concerning mineralization of implants. Immuno-histology showed inhibition of autonomic nerves and lack of implant vascularization in IL-4-/-IL-13-/- mice.

In summery, the two anti-inflammatory cytokines IL-4 and IL-13 influence osteoblast activity and apoptosis in vitro. They also selectively influence cortical bone formation in vivo. These findings suggest a role for IL-4 and IL-13 in osteoblast differentiation, in bone metabolism and in bone formation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 303
Keyword
Medicine, Bone, Osteoblasts, Interleukin-4, Interleukin-13, Knockout, Medicin
Identifiers
urn:nbn:se:uu:diva-8414 (URN)
Public defence
2008-02-15, Rosénsalen, Barnsjukhuset Ingång 95/96, Akademiska Sjukhuset, Uppsala, 09:00
Opponent
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Available from: 2008-01-24 Created: 2008-01-24Bibliographically approved

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Silfverswärd, Carl-JohanLarsson, SuneFrost, AndersNilsson, Olle

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