Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium

Abstract

Inactivating mutations of the SOST (sclerostin) gene are associated with overgrowth and sclerosis of the skeleton. To determine mechanisms by which increased amounts of calcium and phosphorus are accreted to enable enhanced bone mineralization in the absence of sclerostin, we measured concentrations of calciotropic and phosphaturic hormones, and urine and serum calcium and inorganic phosphorus in mice in which the sclerostin (sost) gene was replaced by the β-D-galactosidase (lacZ) gene in the germ line. Knockout (KO) (sost −/− ) mice had increased bone mineral density and content, increased cortical and trabecular bone thickness, and greater net bone formation as a result of increased osteoblast and decreased osteoclast surfaces compared with wild-type (WT) mice. β-Galactosidase activity was detected in osteocytes of sost KO mice but was undetectable in WT mice. Eight-week-old, male sost KO mice had increased serum 1α,25-dihydroxyvitamin D, decreased 24,25-dihydroxyvitamin D, decreased intact fibroblast growth factor 23, and elevated inorganic phosphorus concentrations compared with age-matched WT mice. 25-Hydroxyvitamin D 1α-hydroxylase cytochrome P450 (cyp27B1) mRNA was increased in kidneys of sost KO mice compared with WT mice. Treatment of cultured proximal tubule cells with mouse recombinant sclerostin decreased cyp27B1 mRNA transcripts. Urinary calcium and renal fractional excretion of calcium were decreased in sost KO mice compared with WT mice. Sost KO and WT mice had similar serum calcium and parathyroid hormone concentrations. The data show that sclerostin not only alters bone mineralization, but also influences mineral metabolism by altering concentrations of hormones that regulate mineral accretion.S clerostin, an osteocyte-derived, secreted, cystine-knot protein inhibits bone formation by interacting with and altering the activity of bone morphogenetic proteins (BMPs), low-density lipoprotein-receptor-related protein 5 (LRP 5/6), cysteine-rich protein 61, the receptor tyrosine kinase v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (erb B3), among other proteins (1-12). Inactivating mutations in the human sclerostin gene (SOST) are associated with sclerosteosis (Mendelian Inheritance in Man, MIM 269500) or van Buchem disease (MIM 239100) (6), both of which are characterized by progressive overgrowth and sclerosis of the axial and appendicular skeleton and an increase in bone mineral density (6,13,14). These results are supported by data from sost knockout mice, which have markedly increased bone density (15-17).The physiological adaptations that occur in human sclerosteosis and mouse models of the disease that permit the increased accretion of calcium (Ca) and phosphorus (P) required for bone formation are unknown. For example, it is unknown whether sclerostin influences vitamin D metabolite concentrations, the concentrations of phosphaturic peptides such as fibroblast growth factor 23 (FGF-23), and the renal handling of calcium and phosphorus. It is important to understand the adaptations ...

Features of bone metabolism in diabetes mellitus

“…PHEX снижает FGF-23. Вероятно, склеростин ингибирует PHEX и изменяет про-цессинг FGF-23 [58]. Склеростин и FGF23 могут синхрон-но действовать на почечные канальцы для повышения экскреции кальция и фосфора с мочой, тем самым сни-жая доступность этих элементов для минерализации.…”

Reduced Renal Calcium Excretion in the Absence of Sclerostin Expression

“…While PTH and 1a,25(OH) 2 D decrease fractional excretion of calcium by increasing the efficiency of calcium reabsorption in the DT, sclerostin increases fractional excretion of calcium (the absence of sclerostin expression being associated with a reduced fractional excretion of calcium). 6 Thus, the scheme of adaptations to reductions in calcium intake and resultant downstream alterations in hormones (see Figure 1B for current understanding) may need to be amended to include changes in sclerostin expression (Figure 4). In the modified scheme, reduced sclerostin expression, which result from increases in PTH, [126][127][128][129] effect on Cyp27b1 expression since FGF-23 concentrations are diminished in Sost 2/2 mice along with an increase in serum P i concentrations.…”

“…In the modified scheme, reduced sclerostin expression, which result from increases in PTH, [126][127][128][129] effect on Cyp27b1 expression since FGF-23 concentrations are diminished in Sost 2/2 mice along with an increase in serum P i concentrations. 6 The bonederived FGF-23 is a known suppressor of 25(OH)D-1a-hydroxylase, 116 suggesting that the increase in 1a,25(OH) 2 D concentrations in the absence of sclerostin may have resulted from lower FGF-23 levels. In other words, sclerostin may stimulate FGF-23 release from bone, which suppresses renal 1a,25(OH) 2 D synthesis.…”

“…Mouse models of sclerosteosis have increases in skeletal mass similar to those found in patients with the disease. [6][7][8][9] By using a Sost gene knockout model generated in our laboratory, 6 we have demonstrated that sclerostin, either directly or indirectly, through an alteration in the synthesis of 1a,25-dihydroxyvitamin D (1a, 25 [OH] 2 D), influences renal calcium reabsorption in the kidney.…”

Polymorphisms in the Osteoprotegrin Gene with Risk of Osteoporosis and Urinary Calcium Level in a Chinese Population

“…Geriatrics lacking calcium for long time may have some symptoms, such as premature gomphiasis, teeth obscission, obvious hunchback, height decrease, pain in lumbar spine and cervical spine, constipation, hyposomnia [5,6]. Urinary calcium level (UCL) can reflect the calcium metabolism and bone status [7,8]. Many studies have reported that an increased intake of dietary calcium or a highdairy diet may reduce inflammation, oxidative stress, particularly in over-weighted people, through promoting lipid metabolism and a loss of body fat [3,9].…”