Rictor is required for optimal bone accrual in response to anti-sclerostin therapy in the mouse

Bone
Weiwei SunFanxin Long

Abstract

Wnt signaling has emerged as a major target pathway for the development of novel bone anabolic therapies. Neutralizing antibodies against the secreted Wnt antagonist sclerostin (Scl-Ab) increase bone mass in both animal models and humans. Because we have previously shown that Rictor-dependent mTORC2 activity contributes to Wnt signaling, we test here whether Rictor is required for Scl-Ab to promote bone anabolism. Mice with Rictor deleted in the early embryonic limb mesenchyme (Prx1-Cre;Rictor(f/f), hereafter RiCKO) were subjected to Scl-Ab treatment for 5weeks starting at 4months of age. In vivo micro-computed tomography (μCT) analyses before the treatment showed that the RiCKO mice displayed normal trabecular, but less cortical bone mass than the littermate controls. After 5weeks of treatment, Scl-Ab dose-dependently increased trabecular and cortical bone mass in both control and RiCKO mice, but the increase was significantly blunted in the latter. Dynamic histomorphometry revealed that the RiCKO mice formed less bone than the control in response to Scl-Ab. In addition, the RiCKO mice possessed fewer osteoclasts than normal under the basal condition and exhibited lesser suppression in osteoclast number by Scl-Ab. Consistent w...Continue Reading

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Citations

May 5, 2017·Endocrine Reviews·Wen-Chih LeeClifford J Rosen
Apr 5, 2017·Scientific Reports·Kazumasa MinamiHiroki Yokota
Feb 10, 2018·Bone Research·Jianquan Chen, Fanxin Long
Mar 27, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hong ChenFanxin Long
Nov 15, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Haijian SunDengshun Miao
Aug 17, 2018·Endocrinology and Metabolism·Megan C Moorer, Ryan C Riddle
Nov 18, 2018·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Qian-Yuan WuFeng-Lai Yuan
Nov 27, 2016·Cellular and Molecular Life Sciences : CMLS·Courtney M Karner, Fanxin Long

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