Abstract
The effectiveness of vitamin D3 (cholecalciferol) in counteracting the side effects of glucocorticoid (GC) therapy has been demonstrated previously. Abnormalities in systemic hormonal and local (cytokine) regulation of bone marrow (BM) cells may underlie GC-induced imbalance between osteosynthesis and bone resorption. The cytokine system receptor activator of nuclear factor kappa-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) is considered as an integrating link in the NF-κB-mediated interaction of various cells involved in maintaining osteoblastic-osteoclastic balance, which makes it a pharmacological target for regulation and correction of the bone remodeling process. We studied GC-induced impairments of the RANKL/RANK/OPG axis in BM cells depending on vitamin D bioavailability and whether these changes were mediated by glucocorticoid (GR) and/or vitamin D (VDR) receptors. Female Wistar rats administered with prednisolone (5 mg/kg b.w., 30 days) showed a decrease in the GR protein level and the number of GR-positive BM cells. GC caused a marked elevation of RANKL and RANK levels in BM, while OPG decreased. Flow cytometry data indicated GC-elicited increase in the number of circulating RANK-positive osteoclast precursors (OCPs) in BM, peripheral blood, and spleen. In full accordance with the data that the interaction of RANKL-RANK leads to transcriptional activation of NF-κB and subsequent differentiation of osteoclasts, we found an increase in the level of phosphorylated p65 subunit of NF-κB with a simultaneous decrease in the NF-κB inhibitor (IκB) level. These changes were accompanied by vitamin D insufficiency and downregulated expression of CYP27B1 and VDR, which are responsible for synthesis and hormonal signaling of 1,25(OH)2D. Notably, we observed VDR and RANK co-localization in OCPs. Cholecalciferol co-administration (1,000 IU/kg b.w., 30 days) with prednisolone resulted in elevated GR synthesis in BM. Cholecalciferol prevented prednisolone-elicited disturbances of the RANKL/RANK/OPG, which correlated with improved bioavailability and vitamin D signaling through VDR. This caused the lowering of phosphoNF-κB p65 level and inhibiting NF-κB translocation to the nucleus that could reduce the circulating OCPs pool in BM, peripheral blood, and spleen. Our findings suggest that prednisolone-induced abnormalities in GR and RANKL/RANK/OPG signaling pathways are associated with the impairments of vitamin D auto/paracrine system in BM cells and can be ameliorated by cholecalciferol supplementation.
Highlights
Glucocorticoids (GCs) have been extensively used in clinical applications as an effective therapy for a variety of severe inflammatory and autoimmune disorders [1, 2]
We examined the role of vitamin D3 in the regulation of RANKL/RANK/OPG axis in primary bone marrow (BM) cells and its possible relationship with abnormal interaction between glucocorticoid receptor (GR) and VDR signaling pathways in the BM after chronic administration of synthetic GC prednisolone
It has been found that cholecalciferol had a slight lowering effect on the level of OPG in the BM compared with the action of prednisolone, its ultimate impact on OPG/RANKL was, changed toward normalization
Summary
Glucocorticoids (GCs) have been extensively used in clinical applications as an effective therapy for a variety of severe inflammatory and autoimmune disorders [1, 2]. Deleterious side effects of GCs on multi-system pathways linked to osteoblast and osteoclast differentiation and apoptosis, marrow adipogenesis, mineral, and lipid metabolism are the most prevalent pathological features of glucocorticoidinduced skeletal disorders [4]. It was demonstrated that the differentiation deficiencies of osteoclast precursors (OCPs) may contribute to corticosteroid osteoporosis; the stimulating effect of GCs on these cells have been reported. The latter was limited to the early phase of osteoclast differentiation and the enhanced priming of osteoclast progenitors [bone marrow (BM)-derived monocytes/macrophages] toward differentiation into mature osteoclasts [5]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have