Ovariectomy-induced bone loss in TNFα and IL6 gene knockout mice is regulated by different mechanisms
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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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IL-6 deficiency enhances expression of osteoblast-related genes (Runx2 and Col1a1) and decreases expression of osteoclast-related genes.
“IL-6 deficiency enhances the expression of osteoblast-related genes (Runx2 and Col1a1) and decreases the expression of osteoclast-related genes [82].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [82]
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“It has been suggested that IL-6 deficiency enhances the expression of osteo - blast-related genes (Runx2 and Col1a1) and decreases the expression of osteoclast-related genes [82].”
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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
- Publisher
- Bioscientifica
- 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
- bronze
- doi.org
- 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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