Ovariectomy induced bone loss in TNFα and IL6 knockout mice is regulated by different mechanisms
- Siyi Zhu,
- Hongchen He,
- Chengfei Gao,
- Guojing Luo,
- Ying Xie,
- Haiming Wang,
- Li Tian,
- Chen Xiang,
- Yu Xijie⇑ and
- Chengqi He
- S Zhu, Rehabilitation Medicine Center, Sichuan University West China Hospital, Chengdu, China
- H He, Rehabilitation Medicine Center, Sichuan University West China Hospital, Chengdu, China
- C Gao, Rehabilitation Medicine Center, Sichuan University West China Hospital, Chengdu, China
- G Luo, West China Hospital, Sichuan University, China 610041, Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, Chengdu, China
- Y Xie, West China Hospital, Sichuan University, China 610041, Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, Chengdu, China
- H Wang, Rehabilitation Medicine Center, Sichuan University West China Hospital, Chengdu, China
- L Tian, West China Hospital, Sichuan University, China 610041, Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, Chengdu, China
- C Xiang, West China Hospital, Sichuan University, China 610041, Laboratory of Endocrinology and Metabolism, Department of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, Chengdu, China
- Y Xijie, Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, China
- C He, Rehabilitation Medicine Center, Sichuan University West China Hospital, Chengdu, China
- Correspondence: Yu Xijie, Email: xijieyu{at}hotmail.com
Abstract
Female wild-type (WT), TNFα knockout (TNFα-/-) or IL6 knockout (IL6-/-) mice aged 12 weeks were sham-operated (SHAM) or subjected to OVX and euthanized after 4 weeks. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone marrow stromal cells (BMSCs) from all three groups were induced to differentiate into osteoblasts or osteoclasts. Bone metabolism was assessed by histological analysis and qRT-PCR. OVX significantly increased the body weight only in WT mice and decreased the uterine weight in all three genotypes. 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 up-regulated mRNA expressions of osteoblast related genes (Runx2 and Col1a1) and down-regulated 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 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
- Received 17 September 2017
- Revision received 29 December 2017
- Accepted 15 January 2018
- Accepted Preprint first posted online on 16 January 2018
