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J. Biol. Chem., Vol. 281, Issue 33, 23698-23711, August 18, 2006

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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^¶, and Charles H. Turner¹

From the Department of Orthopedic Surgery, Biomechanics and Biomaterials Research Center, and the Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, the ^¶Howard Hughes Medical Institute and Department of Genetics and Center for Human Genetics, Case School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, 44106 and the ^||Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030

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.

Received for publication, February 1, 2006 , and in revised form, April 25, 2006.

^* This work was supported by National Institutes of Health Grants AR046530 (to C. H. T.) and AR053237 (to A. G. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Indiana University School of Medicine, 1120 South Dr., FH 115, Indianapolis, IN 46202. Tel.: 317-274-3226; Fax: 317-274-3702; E-mail: turnerch{at}iupui.edu.

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