Extracts from tumors causing oncogenic osteomalacia inhibit phosphate uptake in opossum kidney cells

Abstract

In oncogenic osteomalacia (OOM), a tumor produces an unknown substance that inhibits phosphate reabsorption in the proximal tubules. This causes urinary phosphate wasting and, as a consequence, hypophosphatemic osteomalacia. To characterize this poorly understood biological tumor activity we generated aqueous extracts from several OOM tumors. Extracts from three of four tumors inhibited, dose-and time-dependently, 32 Porthophosphate uptake by opossum kidney (OK) cells; maximum inhibition was about 45% of untreated control. Further characterization revealed that the factor is resistant to heat and several proteases, and that it has a low molecular weight. The tumor extracts also stimulated cAMP accumulation in OK cells, but not in osteoblastic ROS 17/2·8 and UMR106 cells, or in LLC-PK1 kidney cells expressing the parathyroid hormone (PTH)/PTHrelated peptide receptor or the PTH-2 receptor. HPLC separation of low molecular weight fractions of the tumor extracts revealed that the flow-through of all three positive tumor extracts inhibited 32 P uptake and stimulated cAMP accumulation in OK cells. Additionally, a second peak with inhibitory activity on phosphate transport, but without cAMP stimulatory activity, was identified in the most potent tumor extract. We have concluded that several low molecular weight molecules with the ability to inhibit phosphate transport in OK cells can be found in extracts from OOM tumors. It remains uncertain, however, whether these are related to the long-sought phosphaturic factor responsible for the phosphate wasting seen in OOM patients.

The Wrickkened Pathways of FGF23, MEPE and PHEX

“…However, these enzymes efficiently abolish the capacity of PTH and parathyroid extracts to inhibit renal phosphate uptake in vitro . Size ultrafiltration experiments also indicate that tumor phosphatonin-minhibin activity is due to small (< 5 kDa) protease-resistant molecules (Miyauchi et al, 1988;Cai et al, 1994;Wilkins et al, 1995;Lajeunesse et al, 1996;Nelson et al, 1996Nelson et al, , 2001Jonsson et al, 2001). These findings are consistent with the notion that the small proteolytically resistant ASARM peptide is a phosphatonin and/or minhibin (Rowe et al, 2004).…”

Recurrent phosphaturic mesenchymal tumour of the temporal bone causing deafness and facial nerve palsy

“…3 Fibroblast growth factor-23 inhibits sodium-phosphate co-transporters in the proximal tubular cells of the kidney in vitro (via a decrease in the sodium phosphate transporter-type 2a (NPT2a) transporters). 4 It has also been shown to inhibit 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Furthermore, mice injected with fibroblast growth factor-23 showed reduced serum phosphorus levels, increased phosphate excretion and features of osteomalacia. 5 Similarly, most phosphaturic mesenchymal tumours have been found to over-express fibroblast growth factor-23, and thus exhibit clinical features of osteomalacia.…”

MEPE has the properties of an osteoblastic phosphatonin and minhibin

“…Indeed, FGF23 and MEPE expression are closely correlated in Hyp [40]. Moreover, a number of investigators have reported small (<5 kDa), uncharacterized, phosphaturic molecules partially purified from OHO conditioned media [35,52,[54][55][56]100]. Remarkably, the phosphaturic activity of these molecules is resistant to inactivation by a number of proteases.…”