Oncogenic osteomalacia: is there a new phosphate regulating hormone?

Abstract

SummaryOncogenic osteomalacia is a syndrome associated with rare, usually mesenchymal tumours, which is characterized by hypophosphataemia, phosphaturia and low concentrations of 1,25-dihydroxyvitamin D. The reversal of clinical and biochemical abnormalities following removal of the tumour, indicates it is the source of a humoral factor that is responsible for these abnormalities. It has been demonstrated that the humoral factor inhibits renal phosphate uptake and reduces 1,25-dihydroxyvitamin D production. Although there is evidence that it may act via parathyroid hormone/parathyroid hormone-related peptide receptors and may be a peptide, the factor has not yet been identified, nor has its relationship to factors involved in X-linked hypophosphataemic rickets been established. We propose unifying hypotheses for the pathogenesis of oncogenic osteomalacia and X-linked hypophosphataemic rickets which involve defects in the PEX gene. These hypotheses do not fully explain all the available data and it remains possible that hormone(s) with little or no role in X-linked hypophosphataemic rickets may be responsible for oncogenic osteomalacia.

Mepe is expressed during skeletal development and regeneration

“…Matrix extracellular phosphoglycoprotein (MEPE, also called OF45) is a novel gene initially identified in oncogenic hypophosphatemic osteomalacia (OHO), a rare syndrome of rickets/ osteomalacia and hypophosphatemia associated with a coexisting tumor (Argiro et al, 2001;Nelson et al, 1997;Petersen et al, 2000;Rowe et al, 2000). MEPE protein shares structural similarity with other bone and dentin mineral matrix phosphoglycoproteins (Rowe et al, 2000)and like these other molecules, is expressed within osteocytes of adult bone (Petersen et al, 2000;Rowe et al, 2000).…”

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

“…Similarly, increased concentration of a phosphaturic factor has been implicated in the pathogenesis of oncogenic osteomalacia (OOM), an acquired condition characterized by phosphopenic osteomalacia due to renal phosphate wasting (Nelson et al 1997, Drezner 2000. Patients affected by OOM exhibit biochemical characteristics that are similar to those observed in XLH patients.…”

Raquitismo e osteomalacia

“…O NPT2 sofre ação inativadora da fosfatonina, um hormônio peptídeo, produzido provavelmente pelos hepatócitos, cuja estrutura molecular não está totalmente identificada (34)(35)(36). O transplante de rins de ratos normais para ratos hipofosfatêmicos e, também, a realização de parabiose entre eles, evidenciou a perda de fosfato pelos rins anteriormente normais, caracterizando a existência desse fator humoral fosfatúrico (49,50).…”

“…O controle dos níveis circulantes de fosfatonina é feito pelo produto protéico do gene PEX, através de inativação proteolítica. Dessa forma, mutações no gene PEX resultam na produção de uma proteína alterada, incapaz de degradar a fosfatonina, dando origem ao quadro clínico e bioquímico do raquitismo hipofosfatêmico (34)(35)(36). Há também evidências da associação de anormalidades intrínsicas dos osteoblastos, colaborando com a formação óssea anormal (36,40).…”

“…As alterações bioquímicas e os quadros clínico e histológico revertem com a retirada do tumor, o qual secreta um fator humoral fosfatúrico e inibidor da atividade da enzima 1a-hidroxilase, com redução da síntese de 1,25(OH) 2 D. Esse fator humoral seria a fosfatonina, ou seja, o mesmo que participa da patogê-nese do raquitismo hipofosfatêmico, que envolve o gene PEX, previamente analisado. Larga variedade de tumores em ossos e tecidos moles foi encontrada associada à patologia: mesenquimais, angiosarcomas, hemangiomas, condrosarcomas, carcinoma de prósta-ta, schwanoma, osteoblastoma, tumores neuroendócrinos e mistos (1)(2)(3)(34)(35)(36). Muitas vezes o diagnóstico é difícil, pois são pequenos e de crescimento lento, não podendo ser localizados ou totalmente removidos.…”