Effects of intermittent parathyroid hormone (PTH) administration on SOST mRNA and protein in rat bone

Abstract

Sclerostin, the secreted protein product of the SOST gene, which is mainly expressed by osteocytes, has recently been proposed as a negative regulator of bone osteoblastogenesis. Chronic elevation of PTH reduces SOST expression by osteocytes, while controversial results have been obtained by intermittent PTH administration. We have investigated the effects of intermittently administered PTH on SOST expression and sclerostin localization, comparing them with those of controls, as they appeared in three different bone segments of rat tibia: secondary trabecular metaphyseal and epiphyseal bone, and cortical diaphyseal bone. The histomorphometric results demonstrate that PTH enhances bone turnover through anabolic effects, as shown by the association of increased bone resorption variables with a significant rise in BV/TV, Tb.Th and Tb.N and a fall in Tb.Sp. PTH induces a SOST mRNA and protein fall in secondary metaphyseal trabeculae, diaphyseal bone and in epiphyseal trabeculae. Numbers of sclerostin immunopositive osteocytes/mm(2) show no change, compared with controls; there are fewer sclerostin-positive osteocytes in secondary metaphyseal trabeculae than in the other two bone areas, both in the control and PTH groups. The low numbers of sclerostin-positive osteocytes in the metaphyseal trabecular bone seem to be directly related to the fact that this area displays a high remodeling rate. The anabolic effects of PTH are in line with the fall of SOST mRNA and protein in all the three bone segments examined; the rise of bone turnover supports a negative role of SOST in bone formation.

Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone

“…At least some of the positive effects of parathyroid hormone on bone formation have been attributed to its ability to moderately down-regulate sclerostin (32)(33)(34). The inability of Scl-AbI to prevent DEXinduced inhibition of growth is therefore consistent with the findings from a study by van Buul-Offers et al (35), in which they showed that parathyroid hormone was also ineffective at reducing GC-mediated growth inhibition (36).…”

Immunolocalization of sclerostin synthesized by osteocytes in relation to bone remodeling in the interradicular septa of ovariectomized rats

“…Another osteocyte-derived factor, sclerostin, is a glycoprotein encoded by the SOST gene [10], and was reported to bind the LRP5/6 receptor, thereby antagonizing Wnt signaling and increasing -catenin degradation [11,12]. Sclerostin has been reported as a negative regulator of osteoblastic bone formation [12][13][14][15]: Sclerostin secreted by osteocytes may pass through the osteocytic canaliculi and inhibit bone-lining osteoblasts. Taken together, osteocytes are not merely resting cells embedded in bone, but appear to be dynamically related to bone metabolism, e.g., by secreting sclerostin.…”

<b>Immunolocalization of osteocyte-derived molecules during bone fracture healing of mouse </b><b>ribs </b>

“…There are reports showing that periosteal mesenchymal cells respond to locally increased levels of growth factors and cytokines, and may differentiate into chondrocytes or osteoblasts (41), so that, the periosteal mesenchymal environment appears to influence such cell fate (4). In spite of the local ef-blastic bone formation (27,31,36), as it is secreted by osteocytes, passes through the osteocytic canaliculi and inhibits the activation of bone-lining osteoblasts. On the other hand, there are reports on FGF23-driven modulation of adequate serum phosphate concentrations, which are required for normal skeletal development as well as preservation of bone integrity (28).…”