Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both.
Although often supersaturated with mineral salts such as calcium phosphate and calcium oxalate, normal urine possesses an innate ability to keep them from forming harmful crystals. This inhibitory activity has been attributed to the presence of urinary macromolecules, although controversies abound regarding their role, or lack thereof, in preventing renal mineralization. Here, we show that 10% of the mice lacking osteopontin (OPN) and 14.3% of the mice lacking Tamm-Horsfall protein (THP) spontaneously form interstitial deposits of calcium phosphate within the renal papillae, events never seen in wild-type mice. Lack of both proteins causes renal crystallization in 39.3% of the double-null mice. Urinalysis revealed elevated concentrations of urine phosphorus and brushite (calcium phosphate) supersaturation in THP-null and OPN/THP-double null mice, suggesting that impaired phosphorus handling may be linked to interstitial papillary calcinosis in THP- but not in OPN-null mice. In contrast, experimentally induced hyperoxaluria provokes widespread intratubular calcium oxalate crystallization and stone formation in OPN/THP-double null mice, while completely sparing the wild-type controls. Whole urine from OPN-, THP-, or double-null mice all possessed a dramatically reduced ability to inhibit the adhesion of calcium oxalate monohydrate crystals to renal epithelial cells. These data establish OPN and THP as powerful and functionally synergistic inhibitors of calcium phosphate and calcium oxalate crystallization in vivo and suggest that defects in either molecule may contribute to renal calcinosis and stone formation, an exceedingly common condition that afflicts up to 12% males and 5% females.
Mo
Lan
L
Dept. of Urology, New York Univ. School of Medicine, Veterans Affairs Medical Center in Manhattan, 423 E23 St., Rm. 18064S, New York, NY 10010, USA. xue-ru.wu@med.nyu.edu
Liaw
Lucy
L
Evan
Andrew P
AP
Sommer
Andre J
AJ
Lieske
John C
JC
Wu
Xue-Ru
XR
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000737:chemistry; D002129:Calcium Oxalate / Q000737:chemistry / Q000378:metabolism; D002130:Calcium Phosphates / Q000737:chemistry / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006959:Hyperoxaluria / Q000652:urine; D007669:Kidney Calculi / Q000235:genetics* / Q000473:pathology; D007679:Kidney Medulla / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009088:Mucoproteins / Q000235:genetics*; D053495:Osteopontin / Q000235:genetics*; D017550:Spectroscopy, Fourier Transform Infrared; D058949:Uromodulin
D002130:Calcium Phosphates; D009088:Mucoproteins; C548613:Umod protein, mouse; D058949:Uromodulin; D053495:Osteopontin; D002129:Calcium Oxalate; D002118:Calcium