Lrp5 functions in bone to regulate bone mass (Nat Med, 2011, 17:684-691)

報告日期: 2012/06/05
報告時間: 17:10/18:00
報告學生: 林摯鈞 (英文報告)
講評老師: 黃國淵
附件下載: 下載[1205-1334225387-1.pdf] 

Lrp5 functions in bone to regulate bone mass

Nat Med. 2011 Jun;17(6):684-91.

Cui Y, Niziolek PJ, MacDonald BT, Zylstra CR, Alenina N, Robinson DR, Zhong Z, Matthes S, Jacobsen CM, Conlon RA, Brommage R, Liu Q, Mseeh F, Powell DR, Yang QM, Zambrowicz B, Gerrits H, Gossen JA, He X, Bader M, Williams BO, Warman ML, Robling AG.

Commentator: Kuo Yuan, Huang                            Date: 2012/06/05

Presenter: Chih-Chun Lin                                       Room: 602

 

Abstract:

    The low-density-lipoprotein receptor-related protein 5 (LRP5) has been implicated in human disorders of low and high bone mass. Loss-of-function mutations cause the autosomal recessive osteoporosis-pseudoglioma syndrome, and heterozygous missense mutations in families segregating autosomal dominant high bone mass (HBM) phenotypes have been identified. Studies in several laboratories indicate that LRP5 can function as a co-receptor in the canonical Wnt signaling cascade in vivo and ex vivo [1, 2]. However, recent report suggested that Lrp5 regulates bone mass via the regulation of peripheral serotonin synthesis in the duodenum [3]. Accordingly, whether LRP5 acts locally via the Wnt signaling pathway or by the mean of peripheral serotonin synthesis needs further investigation. The authors generated mice with osteocyte-specific expression and intestine-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. They found that bone properties in mice with osteocyte-specific expression of Lrp5 mutations were comparable to bone properties in mice with inherited mutations while mice with intestine-specific expression of Lrp5 mutations were not. They also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; and they observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.

References:

  1. 1.      Ai, M., Holmen, S.L., Van Hul, W., Williams, B.O. & Warman, M.L. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol. Cell. Biol. 25, 4946–4955 (2005).
  2. 2.      Semenov, M.V. & He, X. LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. J. Biol. Chem. 281, 38276–38284 (2006).
  3. 3.      Yadav, V.K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).