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Cellular and molecular mechanisms of vitamin D3 protective action on glucocorti-coid-induced osteoporosis


Submitted by Palladin Institute of Biochemistry of the NAS of Ukraine

Authors: Khomenko A.V., Lisakovska O.O., Mazanova A.O.


Glucocorticoids are widely used in medicineas an effective anti-inflammatory, immunosuppressive and anti-allergic drugs. However, their long-term application is associated with the development of various pathologies. The most common side effect is glucocorticoid-induced osteoporosis, a metabolic disease of bone tissue due to disturbances of the bone remodeling. It is known that vitamin D3 (cholecalciferol) plays a key role in the regulation of osteogenesis and mineralization of bone tissue.

The aim of this work was to find out the alterations of vitamin D metabolism, tostudy the relationship between vitamin D level and NF-κB-associated cellular signaling in experimental glucocorticoid-induced osteoporosis, as well as to substantiatethe ways ofcorrection of the revealed side effects. Based on experimental studies the authors have determined that prolonged use of prednisolone caused the development of vitamin D deficiency (by25OHD level in serum) due to the inhibition of vitamin D 25-hydroxylase activity and decreased expression of its isoenzymes CYP27A1 and CYP2R1. Prednisolone also led to the development of oxidative-nitrosative stress in the liver and  induced an increase in the number of apoptotic and necrotic hepatocytes. The effects of prednisolone and cholecalciferol on the state of vitamin D auto/paracrine system in different organs under were firstly described. It was shown the negative influence of glucocorticoid therapy on mineral metabolism, osteosynthesis (based on the content of VDR and osteocalcin) and the biomechanical parameters of bone tissue in experimental animals. We demonstrated multi-directional changes in the cytokine signaling pathway that regulate the process of bone resorption – RANK (receptor activator of nuclear factor ĸB)/ RANKL (RANK ligand)/ OPG (osteoprotegerin, decoy receptor of RANKL) and NF-κB system in bone tissue and bone marrow. The efficacy of the cholecalciferol torestore 25OHD content, correct prednisolone-induced liver disturbances, reduce the pool of circulating osteoclast precursors  and normalize the balance between osteosynthesis and bone resorption were shown. To determine 25OHD as an markerof vitamin D bioavailability, in-house immune diagnostic kit wasdeveloped. We confirmed  that the developed diagnostic kit can be successfully used totest the vitamin D status of the organism in osteoporosis and other pathological conditions.

Publications related to this work: 47,  including 14 articles (4 in international journals). According to the Scopus database, the total number of references to the author’s publications presented in the work is 10, h-index = 2; according to the Google Shcolar database, the total number of references to the author’s publications presented in the work is 21, h-index = 3. Based on the experimental results, 1 PhD thesis was defended.