mTORC2 signaling promotes skeletal growth and bone formation in mice

Journal of Bone and Mineral Research

Volumn 30, Issue 2, 2015, Pages 369-378

  Chen, Jianquan ^a   Holguin, Nilsson ^a   Shi, Yu ^a   Silva, Matthew J ^a   Long, Fanxin ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Bone; Cartilage; Mechanical loading; Mouse; mTORC2; Rictor

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MULTIPROTEIN COMPLEX; TARGET OF RAPAMYCIN KINASE; TOR COMPLEX 2;

ANIMAL CELL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; BONE DEVELOPMENT; BONE GROWTH; BONE MASS; CARTILAGE CELL; CELL PROLIFERATION; CELL SIZE; CONTROLLED STUDY; CORTICAL BONE; EMBRYO; FEMALE; HOMEOSTASIS; HYPERTROPHY; MALE; MESENCHYME; MOUSE; NONHUMAN; OSSIFICATION; OSTEOLYSIS; PERIOSTEUM; TRABECULAR BONE; ANIMAL; BONE; CELL DIFFERENTIATION; CHONDROCYTE; EMBRYOLOGY; MAMMALIAN EMBRYO; MECHANICAL STRESS; METABOLISM; NEWBORN; OSTEOBLAST; PATHOLOGY; PHYSIOLOGY; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION;

ANIMALS; ANIMALS, NEWBORN; BONE AND BONES; CELL DIFFERENTIATION; CELL PROLIFERATION; CHONDROCYTES; EMBRYO, MAMMALIAN; HYPERTROPHY; MICE; MULTIPROTEIN COMPLEXES; OSTEOBLASTS; OSTEOGENESIS; PROTEIN BIOSYNTHESIS; SIGNAL TRANSDUCTION; STRESS, MECHANICAL; TOR SERINE-THREONINE KINASES;

EID: 84921710835     PISSN: 08840431     EISSN: 15234681     Source Type: Journal    
DOI: 10.1002/jbmr.2348     Document Type: Article

References (44)

1. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-93.
2. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005 Feb 18;307(5712):1098-101.
3. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. 2008;416(3):375-85.
4. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6(11):1122-8.
5. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296-302.
6. Hagiwara A, Cornu M, Cybulski N, et al. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 2012;15(5):725-38.
7. Esen E, Chen J, Karner CM, Okunade AL, Patterson BW, Long F. WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation. Cell Metab. 2013;17(5):745-55.
8. Sen B, Xie Z, Case N, et al. mTORC2 regulates mechanically induced cytoskeletal reorganization and lineage selection in marrow-derived mesenchymal stem cells. J Bone Miner Res. 2014;29(1):78-89.
9. Xian L, Wu X, Pang L, et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med. 2012;18(7):1095-101.
10. Long F. Building strong bones: molecular regulation of the osteoblast lineage. Nat Rev Mol Cell Biol. 2012;13(1):27-38.
11. Fulzele K, Riddle RC, DiGirolamo DJ, et al. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell. 2010;142(2):309-19.
12. Long F, Ornitz DM. Development of the endochondral skeleton. Cold Spring Harb Perspect Biol. 2013;5(1):a008334.
13. Maes C, Kobayashi T, Selig MK, et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell. 2010;19(2):329-44.
14. Niziolek PJ, Farmer TL, Cui Y, Turner CH, Warman ML, Robling AG. High-bone-mass-producing mutations in the Wnt signaling pathway result in distinct skeletal phenotypes. Bone. 2011;49(5):1010-9.
15. Li X, Ominsky MS, Niu QT, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. 2008;23(6):860-9.
16. Cui Y, Niziolek PJ, Macdonald BT, et al. Lrp5 functions in bone to regulate bone mass. Nat Med. 2011;17(6):684-91.
17. Lynch ME, Main RP, Xu Q, et al. Tibial compression is anabolic in the adult mouse skeleton despite reduced responsiveness with aging. Bone. 2011;49(3):439-46.
18. Hsieh YF, Turner CH. Effects of loading frequency on mechanically induced bone formation. J Bone Miner Res. 2001;16(5):918-24.
19. Brodt MD, Silva MJ. Aged mice have enhanced endocortical response and normal periosteal response compared with young-adult mice following 1 week of axial tibial compression. J Bone Miner Res. 2010;25(9):2006-15.
20. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283(9):5866-75.
21. Tu X, Rhee Y, Condon KW, et al. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone. 2012;50(1):209-17.
22. Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ. Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis. 2002;33(2):77-80.
23. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell. 2006;11(4):583-9.
24. McLeod MJ. Differential staining of cartilage and bone in whole mouse fetuses by Alcian Blue and Alizarin Red S. Teratology. 1980;22(3):299-301.
25. Long F, Zhang XM, Karp S, Yang Y, McMahon AP. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development. 2001;128(24):5099-108.
26. Long F, Chung UI, Ohba S, McMahon J, Kronenberg HM, McMahon AP. Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton. Development. 2004;131(6):1309-18.
27. Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development. 2005;132(1):49-60.
28. Joeng KS, Long F. The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization. Development. 2009;136(24):4177-85.
29. Chen J, Long F. beta-catenin promotes bone formation and suppresses bone resorption in postnatal growing mice. J Bone Miner Res. 2013;28(5):1160-9.
30. Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res. 2010;25(7):1468-86.
31. Retting KN, Song B, Yoon BS, Lyons KM. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development. 2009;136(7):1093-104.
32. Thoreen CC, Chantranupong L, Keys HR, Wang T, Gray NS, Sabatini DM. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012;485(7396):109-13.
33. Tu X, Joeng KS, Nakayama KI, et al. Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation. Dev Cell. 2007;12(1):113-27.
34. Katagiri T, Yamaguchi A, Komaki M, et al. Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. J Cell Biol. 1994;127(6 Pt 1):1755-66.
35. Lynch ME, Main RP, Xu Q, et al. Cancellous bone adaptation to tibial compression is not sex dependent in growing mice. J Appl Physiol. 2010;109(3):685-91.
36. Holguin N, Brodt MD, Sanchez ME, Kotiya AA, Silva MJ. Adaptation of tibial structure and strength to axial compression depends on loading history in both C57BL/6 and BALB/c mice. Calcif Tissue Int. 2013;93(3):211-21.
37. Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28(1):2-17.
38. Chen J, Long F. mTORC1 signaling controls mammalian skeletal growth through stimulation of protein synthesis. Development. 2014;141(14):2848-54.
39. Chen J, Tu X, Esen E, et al. WNT7B promotes bone formation in part through mTORC1. PLoS Genet. 2014;10(1):e1004145.
40. Riddle RC, Frey JL, Tomlinson RE, et al. Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasis. Mol Cell Biol. 2014;34(10):1850-62.
41. Rodriguez JI, Palacios J, Garcia-Alix A, Pastor I, Paniagua R. Effects of immobilization on fetal bone development. A morphometric study in newborns with congenital neuromuscular diseases with intrauterine onset. Calcif Tissue Int. 1988;43(6):335-9.
42. Jones HH, Priest JD, Hayes WC, Tichenor CC, Nagel DA. Humeral hypertrophy in response to exercise. J Bone Joint Surg. 1977;59(2):204-8.
43. Robling AG, Turner CH. Mechanical signaling for bone modeling and remodeling. Crit Rev Eukaryot Gene Expr. 2009;19(4):319-38.
44. Sawakami K, Robling AG, Ai M, et al. The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. J Biol Chem. 2006;281(33):23698-711.