title: Rictor is required for optimal bone accrual in response to anti-sclerostin therapy in the mouse.
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 with the fewer osteoclasts in vivo, bone marrow stromal cells (BMSC) from the RiCKO mice expressed less Rankl but normal levels of Opg or M-CSF, and were less effective than the control cells in supporting osteoclastogenesis in vitro. The reliance of Rankl on Rictor appeared to be independent of Wnt-β-catenin or Wnt-mTORC2 signaling as Wnt3a had no effect on Rankl expression by BMSC from either control or RICKO mice. Overall, Rictor in the limb mesenchymal lineage is required for the normal response to the anti-sclerostin therapy in both bone formation and resorption.
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Wen-Chih
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Seung-Yon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: flong@wustl.edu.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000375:Aging; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use*; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000473:pathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006023:Glycoproteins / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002352:Carrier Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C486030:Sost protein, mouse; C525637:rictor protein, mouse
keywords: Bone; Osteoblast; Osteoclast; Rictor; Sost; Wnt; mTORC2