CLINICAL CASE 8

In distal tubular cells, this transmembrane protein can break off and circulate as a hormone to alter FGF receptor so that FGF23 can fit right in, " In Greece, she spins the thread of life"?

PTH	1 (5%)
Klotho	15 (83%)
GALNT3	1 (5%)
TRPV5	1 (5%)

The correct answer is Klotho, nice job everyone. TRPV5 is expressed in renal pithelial cells, where it plays an important role in the reabsorption of calcium and loss of TRPV5 in mice leads to hypercalciuria and hyperparathyroidism and bone disease. Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphetemia, inappropriate elevation in 1,25 Vitamin D and painful hyperostosis.  It has been shown that this is due to an inactivating mutations in GALNT3, encoding UDP-N-acetyl alpha D galactosamine polypeptide N acetylgalactosaminyltransferase 3. Some suggests that this protein's genetic alteration can lead to low levels of FGF-23.
Klotho, in Greek mythology spun the thread of life. In the kidney world, klotho is a membrane protein that is expressed in distal kidney tubules, choroid plexus and parathyroid gland. This protein breaks off and circulates as a hormone. It increases FGF23 and it stabalizes TPRV5 so calcium is transported into distal tubular cells. It's role in altering FGF receptor so that FGF23 can bind with great affinity is where it has gained its fame. Its important to learn the actions of FGF-23 as its become a hormone that might be playing a key role in bone metabolism in kidney disease. FGF23 promotes renal phosphate excretion and inhibits 1-alpha hydroxylation of vitamin D in the kidney and increases klotho levels and decreases pTh expresion and secretion. So if you had FGF-23 over expression: you would have hypophosphetemia, osteomalacia,and low 1,25 Vitamin D levels. In contrasts, FGF-23 knockouts would have hyperphosphetemia,high vitamin 1,25 D levels,tumor calcinosis and low klotho levels. When you have klotho knockout, you get hyperphos, high Vitamin 1,25 , early aging calcification, and high FGF-23. 

So basically, phosphate and vitamin D levels can turn FGF23 and klotho to the direction they need to go. Calicum plays a role as well in differentiating it from when pth overrides FGF-23 expression. 

In setting of hypocalcemia and hyperphos, and low Vitamin D:- pth dominates

In setting of hypercalcemia and hyperphos and low Vitamin D:- FGF-23 dominates

The link below from is a great review of the topic using pictures.

The references are listed at the end of the course. A lot still has to be 

clarified in this topic. How this will be used for treatment or monitoring

bone disease, no one really knows yet.