The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment

Kimihiko Sawakami, Alexander G. Robling, Minrong Ai, Nathaniel D. Pitner, Dawei Liu, Stuart J. Warden, Jiliang Li, Peter Maye, David W. Rowe, Randall L. Duncan, Matthew L. Warman, Charles H. Turner

Research output: Contribution to journalArticle

286 Scopus citations

Abstract

The cell surface receptor, low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass. Loss-of-function mutations in LRP5 cause the human skeletal disease osteoporosis-pseudoglioma syndrome, an autosomal recessive disorder characterized by severely reduced bone mass and strength. We investigated the role of LRP5 on bone strength using mice engineered with a loss-of-function mutation in the gene. We then tested whether the osteogenic response to mechanical loading was affected by the loss of Lrp5 signaling. Lrp5-null (Lrp5-/-) mice exhibited significantly lower bone mineral density and decreased strength. The osteogenic response to mechanical loading of the ulna was reduced by 88 to 99% in Lrp5-/- mice, yet osteoblast recruitment and/or activation at mechanically strained surfaces was normal. Subsequent experiments demonstrated an inability of Lrp5-/- osteoblasts to synthesize the bone matrix protein osteopontin after a mechanical stimulus. We then tested whether Lrp5-/- mice increased bone formation in response to intermittent parathyroid hormone (PTH), a known anabolic treatment. A 4-week course of intermittent PTH (40 μg/kg/day; 5 days/week) enhanced skeletal mass equally in Lrp5-/- and Lrp5+/+ mice, suggesting that the anabolic effects of PTH do not require Lrp5 signaling. We conclude that Lrp5 is critical for mechanotransduction in osteoblasts. Lrp5 is a mediator of mature osteoblast function following loading. Our data suggest an important component of the skeletal fragility phenotype in individuals affected with osteoporosis- pseudoglioma is inadequate processing of signals derived from mechanical stimulation and that PTH might be an effective treatment for improving bone mass in these patients.

Original languageEnglish (US)
Pages (from-to)23698-23711
Number of pages14
JournalJournal of Biological Chemistry
Volume281
Issue number33
DOIs
StatePublished - Aug 18 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment'. Together they form a unique fingerprint.

  • Cite this

    Sawakami, K., Robling, A. G., Ai, M., Pitner, N. D., Liu, D., Warden, S. J., Li, J., Maye, P., Rowe, D. W., Duncan, R. L., Warman, M. L., & Turner, C. H. (2006). The Wnt co-receptor LRP5 is essential for skeletal mechanotransduction but not for the anabolic bone response to parathyroid hormone treatment. Journal of Biological Chemistry, 281(33), 23698-23711. https://doi.org/10.1074/jbc.M601000200