Abstract
Osteoporosis is a devastating side effect of chronic glucocorticoid (GC) treatment. Despite the crucial role of vitamin D (VD) in bone homeostasis, the precise molecular mechanisms of its action on GC-induced disturbances of bone remodeling remain undefined. The study was performed to elucidate the relation of VD status to GC-induced changes of the angiogenesis/osteogenesis/bone resorption coupling in bone tissue. Female Wistar rats received prednisolone (5 mg/kg of b.w.) with or without VD3 (1000 IU/kg of b.w., for 30 days). Biomechanical parameters of rat femurs were assessed by the three-point bending test. The levels of calcium, inorganic phosphate, activity of total alkaline phosphatase (ALP), and its isoenzymes were determined spectrophotometrically. Vascular endothelial growth factor-A (VEGF-A) and caspase-3 protein levels were detected by western blotting. Vdr and Cyp27b1 mRNAs were measured by qRT-PCR. Receptor activator of nuclear factor κB (RANK) expression in bone sections was visualized immunohistochemically. Serum 25(OH)D was assayed by ELISA. GC administration led to a decrease in maximal load (by 1.2-fold) and stiffness and toughness (by 1.3-fold), which was accompanied by a 3-fold reduction of 25(OH)D level, an elevation of the ALP bone isoenzyme activity in serum, hypocalcaemia, and hypophosphatemia. Along with prednisolone-induced VD deficiency, an impaired synthesis of Vdr (−30%) and Cyp27b1 (+71%) mRNA was observed, reflecting deregulation of bone tissue VD-auto-/paracrine system. GC caused an increase in caspase-3 content, suppressed the synthesis of the osteoclastic marker RANK, and altered angiogenesis/osteogenesis coupling by significantly reducing the level of VEGF-A.VD3 treatment restored serum 25(OH)D content and the expression of key components of the VD-auto-/paracrine system. VD3 supplementation diminished cell apoptosis and strongly improved angiogenesis/osteogenesis coupling as well as mineral metabolism and biomechanical parameters of femurs in GC-administered rats. Thus, VD3 can have a beneficial effect on the correction of GC-induced pathological changes in bone remodeling.
Highlights
Long-term glucocorticoid (GC) therapy is an effective instrument against a variety of chronic inflammatory diseases
An increase in alkaline phosphatase (ALP) activity could be partially attributed to an increased synthesis of this enzyme in bone tissue, which in turn may be associated with an elevated number of chondrocytes, since glucocorticoids can inhibit osteoblast differentiation and cause osteoblast apoptosis [15]
The results of our study reveal the link between GC-induced impairments of main processes occurring in bone tissue, which underlie the maintenance of healthy bone homeostasis: angiogenesis by assessing the VEGF level, osteoblastogenesis by determining vitamin D receptor (VDR) and CYP27B1, and osteoclastogenesis by RANK labeling
Summary
Long-term glucocorticoid (GC) therapy is an effective instrument against a variety of chronic inflammatory diseases. Us, it is an important theoretical and clinical problem to disclose molecular and cellular mechanisms underlying GC-induced osteoporosis and the ways to correct impairments in the bone tissue function induced by chronic glucocorticoid therapy. E step is the hydroxylation of 25(OH)D at C-1 catalyzed by 25(OH)D1α-hydroxylase (CYP27B1) to form the hormonally active metabolite 1α,25(OH)2D, which is responsible for the biologic action of vitamin D [4]. 1α,25(OH)2D acts via nuclear vitamin D receptor (VDR), regulating the expression of more than 500 genes [6]. Local production of 1α,25(OH)2D and VDR expression in almost all tissues and organs regulate cell growth and differentiation in an autocrine and/or paracrine manner. A significant association has been shown between steroid overload and vitamin D deficiency in a large representative sample of US children and adults [8]
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