title: Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect.
abstract: Megalin is an endocytic receptor highly expressed in the proximal tubules of the kidney. Recently, we demonstrated that this receptor is essential for the renal uptake and conversion of 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3, a central step in vitamin D and bone metabolism. Unfortunately, the perinatal lethality of the conventional megalin knockout mouse model precluded the detailed analysis of the significance of megalin for calcium homeostasis and bone turnover in vivo. Here, we have generated a new mouse model with conditional inactivation of the megalin gene in the kidney by using Cre recombinase. Animals with a renal-specific receptor gene defect were viable and fertile. However, lack of receptor expression in the kidney results in plasma vitamin D deficiency, in hypocalcemia and in severe bone disease, characterized by a decrease in bone mineral content, an increase in osteoid surfaces, and a lack of mineralizing activity. These features are consistent with osteomalacia (softening of the bones) as a consequence of hypovitaminosis D and demonstrate the crucial importance of the megalin pathway for systemic calcium homeostasis and bone metabolism.
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Jörg R
authors.initials: JR
authors.lastname: Leheste
authors.forename: Flemming
authors.initials: F
authors.lastname: Melsen
authors.forename: Maren
authors.initials: M
authors.lastname: Wellner
authors.forename: Pernille
authors.initials: P
authors.lastname: Jansen
authors.forename: Uwe
authors.initials: U
authors.lastname: Schlichting
authors.forename: Ingrid
authors.initials: I
authors.lastname: Renner-Müller
authors.forename: Troels T
authors.initials: TT
authors.lastname: Andreassen
authors.forename: Eckehard
authors.initials: E
authors.lastname: Wolf
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.forename: Anders
authors.initials: A
authors.lastname: Nykjaer
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D005838:Genotype; D006801:Humans; D006996:Hypocalcemia / Q000235:genetics / Q000378:metabolism*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010018:Osteomalacia / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000097:blood / Q000652:urine
chemical_list: D001057:Apolipoproteins E; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D014764:Viral Proteins; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C045073:Cre recombinase; D019426:Integrases