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

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 microg/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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 33 Pg. 23698-711 (Aug 18 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16790443 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anabolic Agents
• LDL-Receptor Related Proteins
• LRP5 protein, human
• Low Density Lipoprotein Receptor-Related Protein-5
• Lrp5 protein, mouse
• Parathyroid Hormone
• Peptide Fragments
• Wnt Proteins

Topics

• Anabolic Agents (administration & dosage)
• Animals
• Body Weight (genetics)
• Bone Density (genetics)
• Bone Remodeling (genetics)
• Bone and Bones (cytology, metabolism, physiology)
• Cell Movement (genetics)
• Cells, Cultured
• Female
• Humans
• LDL-Receptor Related Proteins (deficiency, genetics, physiology)
• Low Density Lipoprotein Receptor-Related Protein-5
• Male
• Mechanotransduction, Cellular (genetics, physiology)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Osteoblasts (metabolism, physiology)
• Osteogenesis (genetics)
• Parathyroid Hormone (administration & dosage)
• Peptide Fragments (administration & dosage)
• Wnt Proteins (metabolism)