title: Reduced renal calcium excretion in the absence of sclerostin expression: evidence for a novel calcium-regulating bone kidney axis.
abstract: The kidneys contribute to calcium homeostasis by adjusting the reabsorption and excretion of filtered calcium through processes that are regulated by parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3). Most of the filtered calcium is reabsorbed in the proximal tubule, primarily by paracellular mechanisms that are not sensitive to calcium-regulating hormones in physiologically relevant ways. In the distal tubule, however, calcium is reabsorbed by channels and transporters, the activity or expression of which is highly regulated and increased by PTH and 1α,25(OH)2D3. Recent research suggests that other, heretofore unrecognized factors, such as the osteocyte-specific protein sclerostin, also regulate renal calcium excretion. Clues in this regard have come from the study of humans and mice with inactivating mutations of the sclerostin gene that both have increased skeletal density, which would necessitate an increase in intestinal absorption and/or renal reabsorption of calcium. Deletion of the sclerostin gene in mice significantly diminishes urinary calcium excretion and increases fractional renal calcium reabsorption. This is associated with increased circulating 1α,25(OH)2D3 levels, whereas sclerostin directly suppresses 1α-hydroxylase in immortalized proximal tubular cells. Thus, evidence is accumulating that sclerostin directly or indirectly reduces renal calcium reabsorption, suggesting the presence of a novel calcium-excreting bone-kidney axis.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; and rkumar@mayo.edu.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Pharmacology, University of California San Diego, and Veterans Affairs San Diego Healthcare System, San Diego, California.
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D005819:Genetic Markers; D005966:Glucuronidase / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007684:Kidney Tubules / Q000378:metabolism*; D000090265:Klotho Proteins; D010281:Parathyroid Hormone / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; C422903:SOST protein, human; C486030:Sost protein, mouse; D014807:Vitamin D; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium
keywords: calcium; parathyroid hormone; vitamin D