Inhibitory effect of aspirin on bone resorption by active vitamin analogues in vitamin D deficient rats

Abstract Background and Aims Active vitamin D analogs and calcimimetics are cornerstones for managing secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). Their direct effects on bone cells remain to be determined. Method Peripheral blood mononuclear cells (PBMCs) of 19 pediatric CKD patients and 6 healthy donors (HD) were differentiated into osteoclasts in presence of M-CSF and RANKL. Effect of combined or single treatment with active vitamin D (1.25-D) and/or the calcimimetic KP2326 were evaluated onto osteoclast differentiation and osteoclast mediated bone resorption. Results 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when CKD worsens. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through an activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited human osteoclast-mediated bone resorption. Conclusion Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however to a different extent. Whilst 1.25-D has no significant effect on bone resorption, KP2326 inhibits bone resorption. Recent data showed that calcimimetics also have a direct anabolic effect on bone, through the stimulation of osteoblastic differentiation and mineralization in human mesenchymal stem cells in vitro. All these results provide a strong rationale for a global positive effect of calcimimetics on bone remodeling. Calcimimetics also significantly decrease FGF23 levels. In the setting of global systematic deleterious effects of high FGF23 levels in CKD, and keeping in mind that active vitamin D analogs stimulate FGF 23 production, all these data could favor the use of decreased doses of 1.25-D with low-doses of calcimimetics in SHPT in dialysis, the combination of these two therapies already being proposed in the 2017 K-DIGO guidelines.

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Circulating vitamin D metabolites and hypercalcaemia of malignancy

Acta Endocrinologica ◽

10.1530/acta.0.1060556 ◽

1984 ◽

Vol 106 (4) ◽

pp. 556-563 ◽

Cited By ~ 36

Author(s):

Stuart H. Ralston ◽

Robert A. Cowan ◽

Andrew G. Robertson ◽

Mary D. Gardner ◽

Iain T. Boyle

Keyword(s):

Vitamin D ◽

Bone Resorption ◽

Primary Hyperparathyroidism ◽

Cancer Patients ◽

Calcium Metabolism ◽

Reliable Method ◽

Plasma Concentrations ◽

Significant Proportion ◽

Vitamin D Metabolites ◽

Active Vitamin

Abstract. Plasma concentrations of 1.25 dihvdroxvcholecalciferol were measured in 44 patients with malignancy associated hvpercalcaemia and related to other hormonal regulators of calcium metabolism. Immunoreactive PTH concentrations were suppressed in all but 2 patients and, as a group, patients with hvpercalcaemia of malignancy had lower 1,25 dihydroxycholecalciferol concentrations than normocalcaemic cancer patients. 1,25 dihydroxycholecalciferol concentrations were clearly detectable in a significant proportion (43%) of hypercalcaemia cases however, suggesting that in these patients the active vitamin D metabolite may contribute to the pathogenesis and maintenance of the hypercalcaemia by stimulating bone resorption, and/or by increasing absorption of calcium from the intestine. Measurement of plasma 1,25 dihydroxycholecalciferol concentration does not provide a wholly reliable method for distinguishing the hypercalcaemia of malignancy from primary hyperparathyroidism.

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Mechanism of inhibitory action of Eldecalcitol, an active vitamin D analog, on bone resorption in vivo

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2012.11.010 ◽

2013 ◽

Vol 136 ◽

pp. 171-174 ◽

Cited By ~ 9

Author(s):

Naoyuki Takahashi

Keyword(s):

Vitamin D ◽

Bone Resorption ◽

Inhibitory Action ◽

Active Vitamin ◽

Active Vitamin D ◽

Vitamin D Analog

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Galectin-3 Contributes to the Inhibitory Effect of lα,25-(OH)2D3 on Osteoclastogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms222413334 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13334

Author(s):

Jianhong Gu ◽

Xueqing Zhang ◽

Chuang Zhang ◽

Yawen Li ◽

Jianchun Bian ◽

...

Keyword(s):

Vitamin D ◽

Bone Resorption ◽

Protein Expression ◽

Active Form ◽

Inhibitory Effect ◽

Mineral Dissolution ◽

Nuclear Factor ◽

Gene And Protein Expression ◽

Galectin 3 ◽

Regulatory Effects

The active form of vitamin D, 1α,25-(OH)2D3, not only promotes intestinal calcium absorption, but also regulates the formation of osteoclasts (OCs) and their capacity for bone mineral dissolution. Gal-3 is a newly discovered bone metabolic regulator involved in the proliferation, differentiation, and apoptosis of various cells. However, the role of galectin-3 (gal-3) in OC formation and the regulatory effects of 1α,25-(OH)2D3 have yet to be explored. To confirm whether gal-3 contributes to the regulatory effects of 1α,25-(OH)2D3 on osteoclastogenesis, osteoclast precursors (OCPs) were induced by macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). TRAP staining and bone resorption analyses were used to verify the formation and activation of OCs. qPCR, Western blotting, co-immunoprecipitation, and immunofluorescence assays were used to detect gene and protein expression. The regulatory effects of gal-3 in OC formation after treatment with 1α,25-(OH)2D3 were evaluated using gal-3 siRNA. The results showed that 1α,25-(OH)2D3 significantly increased gal-3 expression and inhibited OC formation and bone resorption. Expression levels of OC-related genes and proteins, matrix metalloproteinase 9 (MMP-9), nuclear factor of activated T cells 1 (NFATc1), and cathepsin K (Ctsk) were also inhibited by 1α,25-(OH)2D3. Gal-3 knockdown attenuated the inhibitory effects of 1α,25-(OH)2D3 on OC formation, activation, and gene and protein expression. In addition, gal-3 was co-localized with the vitamin D receptor (VDR). These data suggest that gal-3 contributes to the osteoclastogenesis inhibitory effect of lα,25-(OH)2D3, which is involved in bone and calcium homeostasis.

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