Expression of Fibroblast Growth Factor 23, Vitamin D Receptor, and Sclerostin in Bone Tissue from Hypercalciuric Stone Formers

Abstract

Background and objectives Increased bone resorption, low bone formation, and abnormal mineralization have been described in stone formers with idiopathic hypercalciuria. It has been previously shown that the receptor activator of NF-kB ligand mediates bone resorption in idiopathic hypercalciuria (IH). The present study aimed to determine the expression of fibroblast growth factor 23 (FGF-23), vitamin D receptor (VDR), and sclerostin in bone tissue from IH stone formers.Design, setting, participants, & measurements Immunohistochemical analysis was performed in undecalcified bone samples previously obtained for histomorphometry from 30 transiliac bone biopsies of idiopathic hypercalciuria stone-forming patients between 1992 and 2002 and 33 healthy individuals (controls). Serum parameters were obtained from their medical records.Results Histomorphometry disclosed 21 IH patients with high and 9 IH patients with normal bone resorption. Importantly, eroded surfaces (ES/BS) from IH patients but not controls were significantly correlated with VDR immunostaining in osteoblasts (r=0.51; P=0.004), sclerostin immunostaining in osteocytes (r=0.41; P=0.02), and serum 1,25-dihydroxyvitamin D (r=0.55; P,0.01). Of note, both VDR and sclerostin immunostaining were significantly correlated with serum 1,25-dihydroxyvitamin D in IH patients (r=0.52; P=0.01 and r=0.53; P=0.02, respectively), although VDR and sclerostin expression did not differ between IH and controls. IH patients with high bone resorption exhibited a significantly stronger sclerostin immunostaining than IH patients with normal bone resorption. FGF-23 expression in osteocytes from IH patients did not differ from controls and was not correlated with any histomorphometric parameter.Conclusions These findings suggest the contribution of VDR and sclerostin, as well as 1,25-dihydroxyvitamin D, to increase bone resorption in idiopathic hypercalciuria but do not implicate FGF-23 in the bone alterations seen in these patients.

1α,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion

“…Hypervitaminosis D is a condition that leads to excess calcium in the blood; inactivating mutations of the CYP24A1 gene, encoding the vitamin D-24-hydroxylase that degrades 1,25D, have been demonstrated to cause chronic hypercalcaemia (Colussi et al, 2013;Figueres et al, 2015), however levels of sclerostin have not been reported in this condition to date. A positive correlation between sclerostin expression by osteocytes and serum 1,25D levels was recently reported in a cohort of patients suffering hypercalciuria (Menon et al, 2014). Our data suggest that in such conditions, increased 1,25D levels may increase the level of sclerostin production by osteocytes, which in turn may lead to the release of calcium as suggested by the above catabolic mechanisms.…”

Integrative microRNA-gene expression network analysis in genetic hypercalciuric stone-forming rat kidney

“…Activated NF-kappa B translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Menon et al (2014) found that the receptor activator of NF-kappa B ligand mediates bone resorption in IH, while Tozawa et al (2008) reported that oxalate induced OPN expression by activating NF-kappa B in renal tubular cells. But there have been few researches focus on the function of NF-kappa B in the formation of idiopathic hypercalciuria urolithiasis.…”

Demographics and Characterization of 10,282 Randall Plaque-Related Kidney Stones

“… 26 , 28 In addition, VDR activation in osteoclasts has been shown recently to promote bone resorption, increasing thereby calciuria. 27 , 33 …”