Kobayashi Keisuke, Imanishi Yasuo, Koshiyama Hiroyuki, Miyauchi Akimitsu, Wakasa Kenichi, Kawata Takehisa, Goto Hitoshi, Ohashi Hirotsugu, Koyano Hajime M, Mochizuki Ryuichi, Miki Takami, Inaba Masaaki, Nishizawa Yoshiki
Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Life Sci. 2006 Apr 11;78(20):2295-301. doi: 10.1016/j.lfs.2005.09.052. Epub 2005 Dec 7.
Fibrous dysplasia (FD) patients sometimes suffer from concomitant hypophosphatemic rickets/osteomalacia, resulting from renal phosphate wasting. It was recently reported that FD tissue in the patients with McCune-Albright syndrome (MAS) expressed fibroblast growth factor-23 (FGF-23), which is now known to be as a pathogenic phosphaturic factor in patients with oncogenic osteomalacia and X-linked hypophosphatemic rickets. Since it remains controversial whether serum phosphate levels are influenced by FGF23 expressions in FD tissue, isolated FD patients without MAS syndrome were examined for the relationship between FGF23 expressions, circulating levels of FGF-23 and phosphate to negate the effects of MAS-associated endocrine abnormalities on serum phosphate. Eighteen paraffin embedded FD tissues and 2 frozen tissues were obtained for the study. Sixteen of 18 isolated FD tissues were successfully analyzed GNAS gene, which exhibited activated mutations observed in MAS. Eight of 16 FD tissues, which exhibited GNAS mutations, revealed positive staining for FGF-23. These evidence indicate that postzygotic activated mutations of GNAS is necessary for the FD tissue formation by mosaic distribution of mutated osteogenic cell lineage, but is not sufficient to elevate FGF23 expression causing generalized osteomalacia with severe renal phosphate wasting. The expression level of FGF23 in isolated FD tissue with hypophosphatemic osteomalacia determined by real-time PCR was abundant close to the levels in OOM tumors. Osteoblasts/osteocytes in woven bone were predominant source of circulating FGF-23 in FD tissues by immunohistochemistry. A negative correlation of the intensity of FGF-23 staining with serum inorganic phosphate levels indicated that the expression of FGF23 in focal FD tissues could be a prominent determinant of serum phosphate levels in isolated FD patient. These data provide novel insights into the regulatory mechanism of serum inorganic phosphate levels in isolated FD patients and extend the notion that FGF-23 originating from FD tissue may cause hypophosphatemia not only in isolated FD patients but also in the patients with MAS syndrome.
骨纤维发育不良（FD）患者有时会并发低磷性佝偻病/骨软化症，这是由肾脏排磷所致。最近有报道称，McCune - Albright综合征（MAS）患者的FD组织表达成纤维细胞生长因子23（FGF - 23），现在已知其为致癌性骨软化症和X连锁低磷性佝偻病患者的致病性排磷因子。由于FD组织中FGF23表达是否影响血清磷水平仍存在争议，因此对无MAS综合征的孤立性FD患者进行了研究，以探讨FGF23表达、循环中FGF - 23水平与磷之间的关系，从而排除MAS相关内分泌异常对血清磷的影响。本研究获取了18个石蜡包埋的FD组织和2个冷冻组织。18个孤立性FD组织中有16个成功分析了GNAS基因，发现其存在MAS中观察到的激活突变。16个显示GNAS突变的FD组织中有8个FGF - 23染色呈阳性。这些证据表明GNAS的合子后激活突变对于通过突变的成骨细胞谱系的镶嵌分布形成FD组织是必要的，但不足以升高FGF23表达导致伴有严重肾脏排磷的全身性骨软化症。通过实时PCR测定，伴有低磷性骨软化症的孤立性FD组织中FGF23的表达水平很高，接近骨软化症肿瘤中的水平。免疫组织化学显示，编织骨中的成骨细胞/骨细胞是FD组织中循环FGF - 23的主要来源。FGF - 23染色强度与血清无机磷水平呈负相关，表明局灶性FD组织中FGF23的表达可能是孤立性FD患者血清磷水平的一个重要决定因素。这些数据为孤立性FD患者血清无机磷水平的调节机制提供了新的见解，并扩展了源自FD组织的FGF - 23不仅可能导致孤立性FD患者而且可能导致MAS综合征患者发生低磷血症的观念。
