Where Wnts Went: The Exploding Field of Lrp5 and Lrp6 Signaling in Bone

Abstract

Wnt signaling has emerged as a central regulator of skeletal modeling and remodeling. Loss- or gain-of-function mutations in two Wnt co-receptors, Lrp5 and (more recently) Lrp6, have drawn attention to the importance of the Wnt pathway in bone biology. This review summarizes our current understanding of how the Wnt pathway operates on bone and the implications this has for skeletal physiology and drug discovery. Over the past 9 yr, rapid advances have been made in our understanding of the cellular targets for Wnt signaling and of the important regulatory molecules in this metabolic pathway. Both canonical and noncanonical signaling pathways seem to be important for mediating the effects of Wnt in bone. A rapidly expanding catalog of genetically engineered mice has been used to establish the importance of downstream effector molecules (such as β-catenin) in the Wnt pathway, as well as the critical role of endogenous inhibitors of Wnt signaling (such as Dkk1 and sclerostin) in bone metabolism. Indeed, regulation of sclerostin in osteocytes is emerging as an important final pathway for regulating bone anabolism in response to diverse trophic stimuli, from mechnotransduction to the anabolic actions of PTH. From the outset, it had been assumed that the effects of Wnt signaling in bone were caused by direct actions in osteoblast precursors, osteoblasts, and osteocytes. However, startling recent findings have challenged this view and suggest that a key target, at least in mice, is the duodenal enterochromaffin cell. There, Wnt signaling transduced by Lrp5 regulates serotonin synthesis, which acts in an endocrine fashion to regulate bone cell metabolism. It will take time to reconcile this new information with the considerable body of information we already have regarding the actions of Wnt in bone. The Wnt pathway has rapidly emerged as a therapeutic target for drug discovery. Neutralizing antibodies and small-molecule inhibitors of endogenous Wnt inhibitors have shown early promise as bone anabolic agents. However, given the central role of the Wnt pathway in regulating growth and development in extraskeletal tissues, as well as our still rudimentary understanding of how this signaling cascade actually affects bone metabolism, considerable work will be needed to ensure the safety of these new therapies.

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    Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, Orwoll E, Bliziotes MM. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007;167:1246-1251.

    Not in our library10.1001/archinte.167.12.1246

76. 76.

    Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, Goltzman D. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167:188-194.

    Not in our library10.1001/archinte.167.2.188

77. 77.

    Li X, Warmington K, Niu QT, Grisanti M, Tan H, Dwyer D, Stolina M, Simonet WS, Kostenuik PJ, Paszty C, Ke HZ. Increases in BMD observed with anti-sclerostin antibody treatment are reversible: A longitudinal ovariectomized rat study. J Bone Miner Res. 2008;23:S60.

    Not in our library

78. 78.

    Padhi D, Stouch B, Jang G, Fang L, Darling M, Glise H, Robinson M, Harris S, Posvar E. Anti-sclerostin antibody increases markeres of bone formation in healthy postmenopausal women. J Bone Miner Res. 2007;22(S1):S37.

    Not in our library

79. 79.

    Glantschnig H, Hampton R, Wei N, Scott K, Nantermet P, Zhao J, Chen F, Fisher J, Su Q, Pennypacker B, Cusick T, Sandhu P, Reszka A, Strohl W, Flores O, Wang F, Kimmel D, An Z. Fully human anti-DKK1 antibodies increase bone formation and resolve osteopenia in mouse models of estrogen-deficiency induced bone loss. J Bone Miner Res. 2008;23:S60.

    Not in our library

80. 80.

    Bodine PV, Stauffer B, Ponce-de-Leon H, Bhat RA, Mangine A, Seestaller-Wehr LM, Moran RA, Billiard J, Fukayama S, Komm BS, Pitts K, Krishnamurthy G, Gopalsamy A, Shi M, Kern JC, Commons TJ, Wilson MA, Welmaker GS, Trybulski EJ, Moore WJ. A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein (SFRP)-1 stimulates bone formation. J Bone Miner Res. 2007;22(S1):S4.

    Not in our library

81. 81.

    Wan M, Yang C, Li J, Wu X, Yuan H, Ma H, He X, Nie S, Chang C, Cao X. Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev. 2008;22:2968-2979.

    Not in our library10.1101/gad.1702708

82. 82.

    Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone. 2005;37:148-158.

    Not in our library10.1016/j.bone.2005.03.018

83. 83.

    Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456-469.

    Not in our library10.1016/j.cell.2007.05.047

84. 84.

    Lindvall C, Bu W, Williams BO, Li Y. Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev. 2007;3:157-168.

    Not in our library10.1007/s12015-007-0025-3

Cited by papers we hold 4

• Annexin A6 regulates catabolic events in articular chondrocytes via the modulation of NF-κB and Wnt/ß-catenin signaling. · 2018
  Not checked
• WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity · 2010
  No notice
• The Wnt Receptor, Lrp5, Is Expressed by Mouse Mammary Stem Cells and Is Required to Maintain the Basal Lineage · 2009
  No notice
• Lrp4, a Novel Receptor for Dickkopf 1 and Sclerostin, Is Expressed by Osteoblasts and Regulates Bone Growth and Turnover In Vivo · 2009
  No notice

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