The Wnt Co-receptor LRP5 Is Essential for Skeletal Mechanotransduction but Not for the Anabolic Bone Response to Parathyroid Hormone Treatment

• Published in: The Journal of biological chemistry 2006-08, Vol.281 (33), p.23698-23711
• Main Authors: Sawakami, Kimihiko, Robling, Alexander G., Ai, Minrong, Pitner, Nathaniel D., Liu, Dawei, Warden, Stuart J., Li, Jiliang, Maye, Peter, Rowe, David W., Duncan, Randall L., Warman, Matthew L., Turner, Charles H.
• Format: Article
• Language: English
• Subjects: Anabolic Agents - administration & dosage; Animals; Body Weight - genetics; Bone and Bones - cytology; Bone and Bones - metabolism; Bone and Bones - physiology; Bone Density - genetics; Bone Remodeling - genetics; Cell Movement - genetics; Cells, Cultured; Female; Humans; LDL-Receptor Related Proteins - deficiency; LDL-Receptor Related Proteins - genetics; LDL-Receptor Related Proteins - physiology; Low Density Lipoprotein Receptor-Related Protein-5; Male; Mechanotransduction, Cellular - genetics; Mechanotransduction, Cellular - physiology; Mice; Mice, Knockout; Mice, Transgenic; Osteoblasts - metabolism; Osteoblasts - physiology; Osteogenesis - genetics; Parathyroid Hormone - administration & dosage; Peptide Fragments - administration & dosage; Wnt Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M601000200

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.