Alterations in vitamin D metabolite, parathyroid hormone and fibroblast growth factor-23 concentrations in sclerostin-deficient mice permit the maintenance of a high bone mass

Abstract

Humans with mutations of the sclerostin (Sost) gene, and knockout animals in which the Sost gene has been experimentally deleted, exhibit an increase in bone mass. We review the mechanisms by which Sost knockout mice are able to accrete increased amount of calcium and phosphorus required for the maintenance of a high bone mass. Recently published information from our laboratory, shows that bone mass is increased in Sost-deficient mice through an increase in osteoblast, and a decrease in osteoclast activity, which is mediated by activation of β-catenin and an increase in prostacyclin synthesis in osteocytes and osteoblasts. The increases in calcium and phosphorus retention required for enhanced bone mineral accretion are brought about by changes in the vitamin D endocrine system, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Thus, in Sost knockout mice, concentrations of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) are increased and concentrations of PTH and FGF-23 are decreased thereby allowing a positive calcium and phosphorus balance. Additionally, in the absence of Sost expression, urinary calcium is decreased, either through a direct effect of sclerostin on renal calcium handling, or through its effect on the synthesis of 1,25(OH)2D. Adaptations in vitamin D, PTH and FGF-23 physiology occur in the absence of sclerostin expression and mediate increased calcium and phosphorus retention required for the increase in bone mineralization.

Elevated Bone Remodeling Markers of CTX and P1NP in Addition to Sclerostin in Patients with X-linked Hypophosphatemia: A Cross-Sectional Controlled Study

“…HYP mice that are murine homologs of XLH with a similar phenotype of hypophosphatemia, increased FGF-23, renal phosphate wasting and rickets/osteomalacia also have increased sclerostin in the circulation [26] as well as increased Sost mRNA expression (the gene coding for sclerostin) in the long bones [27]. On the contrary, mice with an inactivating mutation in Sost present with a phenotype of skeletal overgrowth and sclerostosis but also have decreased FGF-23, increased levels of phosphate and increased 1,25 dihydroxyvitamin D compared to wildtype mice [28]. Thus apart from regulating osteoblastic bone formation sclerostin also regulates mineral homeostasis of phosphate and calcium.…”

Chronic Psychosocial Stress Impairs Bone Homeostasis: A Study in the Social Isolation Reared Rat

“…Indeed, sclerostin is known to be predominately expressed by osteocytes, displaying anti-anabolic effects on bone formation ( Gooi et al, 2010 ; Atkins et al, 2011 ; Kogawa et al, 2013 ; Compton and Lee, 2014 ). In this regard, sclerostin knockout mice have been demonstrated to exhibit an increase in bone mass ( Lewiecki, 2014 ; Ryan et al, 2015 ).…”

Sclerostin as a novel marker of bone turnover in athletes

“…Sclerostin changes bone mass through alterations in osteocyte and osteoblast Wnt and prostacyclin signalling pathways [ 11 ]. 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 [ 12 ].…”