title: 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.affiliation: Department of Orthopedic Surgery, Biomechanics and Biomaterials Research Center, Indiana University School of Medicine, Indianapolis 46202, USA.
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Sawakami
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Robling
authors.forename: Minrong
authors.initials: M
authors.lastname: Ai
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Pitner
authors.forename: Dawei
authors.initials: D
authors.lastname: Liu
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Warden
authors.forename: Jiliang
authors.initials: J
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Maye
authors.forename: David W
authors.initials: DW
authors.lastname: Rowe
authors.forename: Randall L
authors.initials: RL
authors.lastname: Duncan
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.forename: Charles H
authors.initials: CH
authors.lastname: Turner
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage*; D000818:Animals; D001835:Body Weight / Q000235:genetics; D015519:Bone Density / Q000235:genetics; D016723:Bone Remodeling / Q000235:genetics; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism* / Q000502:physiology; D010012:Osteogenesis / Q000235:genetics; D010281:Parathyroid Hormone / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D045930:Anabolic Agents; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D051153:Wnt Proteins