Cited by 44Bone Metabolism and DiseasesBone health and osteoporosis researchEstrogen and related hormone effects

Ovariectomy-induced bone loss in TNFα and IL6 gene knockout mice is regulated by different mechanisms

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Zhu, Siyi, He, Hongchen, Gao, Chengfei, Luo, Guojing, Xie, Ying, Wang, Haiming, Tian, Li, Chen, Xiang +2 more·2018·Journal of Molecular Endocrinology

Abstract

We examined the effects of tumor necrosis factor-α (TNFα) and interleukin-6 (IL6) gene knockout in preserving the bone loss induced by ovariectomy (OVX) and the mechanisms involved in bone metabolism. Twenty female wild-type (WT), TNFα -knockout (TNFα −/− ) or IL6- knockout (IL6 −/− ) mice aged 12 weeks were sham-operated (SHAM) or subjected to OVX and killed after 4 weeks. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone marrow stromal cells (BMSCs) from all three groups (WT, TNFα −/− and IL6 −/− ) were induced to differentiate into osteoblasts or osteoclasts and treated with 17-β-estradiol. Bone metabolism was assessed by histological analysis, serum analyses and qRT-PCR. OVX successfully induced a high turnover in all mice, but a repair effect was observed in TNFα −/− and IL6 −/− mice. The ratio of femoral trabecular bone volume to tissue volume, trabecular number and trabecular thickness were significantly decreased in WT mice subjected to OVX, but increased in TNFα −/− mice (1.62, 1.34, 0.27-fold respectively; P < 0.01) and IL6 −/− mice (1.34, 0.80, 0.22-fold respectively; P < 0.01). Furthermore, we observed a 29.6% increase in the trabecular number in TNFα −/− mice when compared to the IL6 −/− mice. Both, TNFα −/− and IL6 −/− BMSCs exhibited decreased numbers of TRAP-positive cells and an increase in ALP-positive cells, with or without E2 treatment ( P < 0.05). While the knockout of TNFα or IL6 significantly upregulated mRNA expressions of osteoblast-related genes ( Runx2 and Col1a1 ) and downregulated osteoclast-related mRNA for TRAP , MMP9 and CTSK in vivo and in vitro , TNFα knockout appeared to have roles beyond IL6 knockout in upregulating Col1a1 mRNA expression and downregulating mRNA expressions of WNT-related genes ( DKK1 and Sost ) and TNF-related activation-induced genes ( TRAF6 ). TNFα seemed to be more potentially invasive in inhibiting bone formation and enhancing TRAF6-mediated osteoclastogenesis than IL6, implying that the regulatory mechanisms of TNFα and IL6 in bone metabolism may be different.

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Authors
Zhu, S., He, H., Gao, C., Luo, G., Xie, Y., Wang, H., Tian, L., Chen, X., Yu, X., & He, C.
Affiliations
  • Sichuan University (CN)
  • Hong Kong Polytechnic University (HK)
Corresponding author
Yu, Xijie
Venue
Journal of Molecular Endocrinology
Published
2018-04
Volume
60
Issue
3
Pages
185-198
ISSN
  • 0952-5041 (ISSN-L)
  • 1479-6813
OpenAlex
W2783130811
Cited by
44
References
71
Citations by year
2026: 1 · 2025: 6 · 2024: 3 · 2023: 13 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 2 · 2018: 1
FWCI
1.33
Type
journal article
Language
en
Open access
Locations
  • Journal of Molecular Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PolyU Institutional Research Archive (Hong Kong Polytechnic University) (submittedVersion)
Funders
  • National Natural Science Foundation of China (81572639, 81572236, 81770875, -HM01-, 81372110, 81370969)
  • Southwest Medical University
  • Specialized Research Fund for the Doctoral Program of Higher Education of China (20130181110066)
  • West China Hospital, Sichuan University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
interleukin-6, ovariectomy, bone loss, postmenopausal osteoporosis, bone metabolism, mesenchymal stem cells, osteogenic differentiation, osteoclastogenesis, trabecular bone microarchitecture, knockout mice, estrogen, Wnt signaling, TRAF6, DKK1, sclerostin, COL1A1, Runx2
MeSH terms
Cancellous Bone, Animals, Bone Resorption, Cell Differentiation, Female, Femur, Mice, Inbred C57BL, Models, Biological, Osteoblasts, Osteoclasts, Osteogenesis, Ovariectomy, Tumor Necrosis Factor-alpha, Interleukin-6, Mice, Knockout, Gene Knockout Techniques

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