Tumors Associated With Oncogenic Osteomalacia Express Genes Important in Bone and Mineral Metabolism

Abstract

ABSTRACT

MEPE has the properties of an osteoblastic phosphatonin and minhibin

“…MEPE expression occurs in all OHO tumors screened and is notably absent in non-phosphaturic tumors [15,71,79,81]. The exclusive osteoblast expression profile of MEPE, its temporal expression with PHEX, its marked up-regulation in HYP, its presence as a secreted protein in serum and matrix, the coordinate down-regulation of MEPE expression by PHEX and 1,25-dihydroxy vitamin-D 3 , and the overexpression and secretion by OHO tumors indicated to us that MEPE is a good candidate for an OB-PTN [2,3,15,26,29,50,71,79,81].…”

“…There is overwhelming evidence implicating the osteoblast as the cell intrinsically defective [13,18,[20][21][22]30,37,50,58,59,67,69,80,101,102] and the HYP osteoblast directly secretes factors (phosphatonins) that impact adversely on renal phosphate uptake and mineralization in vivo and in vitro. FGF23 activating mutations are responsible for the changes in phosphate, vitamin D metabolism and mineralization in ADHR [4,82,97,98] and overexpression of wild-type FGF23 in some but not all OHO tumors is directly or indirectly responsible for the changes in some tumor-induced osteomalacias [15,81,97,99]. Also, a number of groups have reported lack of FGF23 expression in bone/osteoblasts [3,27,29,41,98,104] and others using more sensitive techniques have detected low levels of FGF23 mRNA in bone tissue but not in normal murine osteoblasts [40].…”

“…This was achieved by expression screening of an OHO tumor cDNA library with polyclonal antibodies that neutralized OHO tumor secreted phosphate uptake-inhibiting factor(s) [71]. MEPE is exclusively expressed in osteoblasts, osteocytes and odontoblasts and markedly up-regulated in murine X-linked hypophosphatemic rickets (Hyp) osteoblasts and OHO tumors [2,3,15,26,29,45,62,71]. The primary defect in HYP is due to mutations and functional inactivation of the gene product PHEX resulting in defective calcification of bone, renal phosphate wasting (hypophosphatemia) and abnormal vitamin D metabolism [33,72,74].…”

“…The specific ADHR mutations increase the stability of mutated FGF23 and the uncleaved mutated molecule is phosphaturic and elicits osteomalacia/rickets [4,77,81,98]. Wild-type FGF23 is also expressed in OHO tumors and the tumor over-expression of the wild-type FGF23 molecule is thought to swamp proteolytic mechanisms that normally inactivate full-length FGF23 [11,15,81]. Evidence suggests, however, that other factors may also play a role in this complex bone-renal pathway.…”

“…MEPE is a secreted RGD-matrix phosphoglycoprotein up-regulated in OHO tumors and Hyp osteoblasts. Moreover, MEPE is exclusively expressed in osteoblasts, osteocytes and odontoblasts [2,3,15,26,29,62,71,79,81]. MEPE also belongs to the short integrin-binding ligand interacting glycoprotein (SIBLING) family that all map to 4q21.1 [24,71].…”