PMID- 29339399 OWN - NLM STAT- MEDLINE DCOM- 20190913 LR - 20190913 IS - 1479-6813 (Electronic) IS - 0952-5041 (Linking) VI - 60 IP - 3 DP - 2018 Apr TI - Ovariectomy-induced bone loss in TNFalpha and IL6 gene knockout mice is regulated by different mechanisms. PG - 185-198 LID - 10.1530/JME-17-0218 [doi] AB - We examined the effects of tumor necrosis factor-alpha (TNFalpha) 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), TNFalpha-knockout (TNFalpha(-/-)) 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, TNFalpha(-/-) and IL6(-/-)) were induced to differentiate into osteoblasts or osteoclasts and treated with 17-beta-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 TNFalpha(-/-) 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 TNFalpha(-/-) 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 TNFalpha(-/-) mice when compared to the IL6(-/-) mice. Both, TNFalpha(-/-) 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 TNFalpha 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, TNFalpha 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). TNFalpha seemed to be more potentially invasive in inhibiting bone formation and enhancing TRAF6-mediated osteoclastogenesis than IL6, implying that the regulatory mechanisms of TNFalpha and IL6 in bone metabolism may be different. CI - (c) 2018 Society for Endocrinology. FAU - Zhu, Siyi AU - Zhu S AD - Rehabilitation Medicine CenterWest China Hospital, Sichuan University, Chengdu, China. AD - Rehabilitation Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University, Chengdu, China. AD - Laboratory of Endocrinology and MetabolismDepartment of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. FAU - He, Hongchen AU - He H AD - Rehabilitation Medicine CenterWest China Hospital, Sichuan University, Chengdu, China. FAU - Gao, Chengfei AU - Gao C AD - Rehabilitation Medicine CenterWest China Hospital, Sichuan University, Chengdu, China. AD - Rehabilitation Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University, Chengdu, China. AD - Institute for Disaster Management and ReconstructionSichuan University-The Hong Kong Polytechnic University, Chengdu, China. FAU - Luo, Guojing AU - Luo G AD - Laboratory of Endocrinology and MetabolismDepartment of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. FAU - Xie, Ying AU - Xie Y AD - Laboratory of Endocrinology and MetabolismDepartment of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. FAU - Wang, Haiming AU - Wang H AD - Rehabilitation Medicine CenterWest China Hospital, Sichuan University, Chengdu, China. AD - Rehabilitation Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University, Chengdu, China. FAU - Tian, Li AU - Tian L AD - Laboratory of Endocrinology and MetabolismDepartment of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. FAU - Chen, Xiang AU - Chen X AD - Laboratory of Endocrinology and MetabolismDepartment of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. FAU - Yu, Xijie AU - Yu X AD - Laboratory of Endocrinology and MetabolismDepartment of Endocrinology, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China xijieyu@hotmail.com hxkfhcq2015@126.com. FAU - He, Chengqi AU - He C AD - Rehabilitation Medicine CenterWest China Hospital, Sichuan University, Chengdu, China xijieyu@hotmail.com hxkfhcq2015@126.com. AD - Rehabilitation Key Laboratory of Sichuan ProvinceWest China Hospital, Sichuan University, Chengdu, China. AD - Institute for Disaster Management and ReconstructionSichuan University-The Hong Kong Polytechnic University, Chengdu, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180116 PL - England TA - J Mol Endocrinol JT - Journal of molecular endocrinology JID - 8902617 RN - 0 (Interleukin-6) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - Bone Resorption/*genetics/*pathology MH - Cancellous Bone/pathology MH - Cell Differentiation MH - Female MH - Femur/pathology MH - Gene Knockout Techniques MH - Interleukin-6/deficiency/*genetics/metabolism MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Models, Biological MH - Osteoblasts/metabolism/pathology MH - Osteoclasts/metabolism/pathology MH - Osteogenesis MH - *Ovariectomy MH - Tumor Necrosis Factor-alpha/deficiency/*genetics/metabolism OTO - NOTNLM OT - IL6 OT - TNFalpha OT - bone metabolism OT - osteoblasts OT - osteoclasts OT - osteoporosis EDAT- 2018/01/18 06:00 MHDA- 2019/09/14 06:00 CRDT- 2018/01/18 06:00 PHST- 2017/12/29 00:00 [received] PHST- 2018/01/15 00:00 [accepted] PHST- 2018/01/18 06:00 [pubmed] PHST- 2019/09/14 06:00 [medline] PHST- 2018/01/18 06:00 [entrez] AID - JME-17-0218 [pii] AID - 10.1530/JME-17-0218 [doi] PST - ppublish SO - J Mol Endocrinol. 2018 Apr;60(3):185-198. doi: 10.1530/JME-17-0218. Epub 2018 Jan 16.