Nongenotropic, Anti-Apoptotic Signaling of 1α,25(OH)2-Vitamin D3 and Analogs through the Ligand Binding Domain of the Vitamin D Receptor in Osteoblasts and Osteocytes

Abstract

Changes in the birth or death of osteoblasts and/or osteoclasts represent fundamental pathophysiologic changes in most acquired metabolic bone diseases, including the osteoporosis that results from sex steroid deficiency, glucocorticoid excess, or old age (1-6). Furthermore, pharmacotherapeutics used commonly for the treatment of metabolic bone diseases exert their beneficial effects on bone by regulating the rate of birth of new osteoclasts or osteoblasts or their apoptosis (6 -8).We have recently shown that estrogens and androgens, acting via their classical nuclear receptors (ER␣, 1 ER␤, or AR), attenuate the apoptosis of several different cell types, including osteoblasts and osteocytes, by rapidly activating the Src/Shc/ ERK and phosphatidylinositol 3-kinase (PI3K) and down-regulating the JNK signaling pathways. This effect requires only the ligand binding, not the DNA binding, domain of the receptor, and, unlike its classical transcriptional action, it is eliminated by nuclear targeting of the receptor (9). Activation of ERKs leads to the rapid translocation of the kinases into the nucleus where they phosphorylate common transcription factors like Elk-1, CCAAT enhancer-binding protein-␤, and cAMPresponse element-binding protein. These transcription factors in turn up-regulate gene expression, as exemplified by the up-regulation of the early growth response-1 protein gene, an ERK/serum response element target gene. Likewise, suppression of the JNK signaling cascade by sex steroids leads to downregulation of c-Jun expression (10). We have earlier used a ligand that potently and selectively activates nongenotropic actions of the classical ER or AR and thereby activates kinases and their downstream transcription factors and target genes with only minimal effects on classical estrogen response element-mediated genotropic transcription. Furthermore, we have demonstrated that, although such classical genotropic actions of sex steroid receptors are essential for their effects on reproductive tissues, they are dispensable for their bone protective effects (2).

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

“…First, the increased ratio of NCoR1 to VDR may drive apo receptor complexes to assemble on the promoter/enhancer region of target genes and, therefore, form a template for subsequent more stable epigenetic silencing of these regions. Second, it may allow cytoplasmic VDR actions to suppress apoptosis via nontranscriptional interactions (49). Elevation of NCoR1 and NCoR2/SMRT found in the current study may in part explain the relative insensitivity of other breast cancer cell lines (BT-474, BT-20, HBL-100, and SK-BR-6) found by others (18,50).…”

AKT Pathway is Activated by 1,25-Dihydroxyvitamin D3 and Participates in its Anti-Apoptotic Effect and Cell Cycle Control in Differentiating HL60 Cells

“…A similar dichotomy exists in murine cells; 1,25D and analogs reduce P-AKT levels in squamous cell carcinoma cells and endothelial cells [30][31][32] while in murine fibroblasts, osteoblasts and osteoclasts 1,25D activates AKT and is anti-apoptotic. 33,34 In the experiments presented here we observed that inhibition of the PI3K/AKT by LY294002 or Wortmannin resulted in cell death by apoptosis which was attenuated by 1,25D (Figs. 3 and 4).…”

“…1 Also, androgens are known to be major growth and survival factors for normal prostate cells, 2 while the vitamin/ hormone 1,25-dihydroxyvitamin D 3 (1,25D) induces both differentiation and increased survival of several types of cells, including hematopoietic cells, 3,4 primary human keratinocytes, 5 and murine osteoblastic cells. 6 While increased survival is a desirable feature of normal differentiating cells, it may confound the design of differentiation therapy for neoplastic diseases. Vitamin D analogs have been tested in several Phase 1 and Phase 2 cancer therapy trials without a major success, and consequently further evaluation of these compounds as cancer therapeutic agents is expected to focus on the efficacy of combining vitamin D analogs with other compounds, including cytotoxic drugs.…”

1α,25-Dihydroxyvitamin D3 antiproliferative actions involve vitamin D receptor-mediated activation of MAPK pathways and AP-1/p21waf1 upregulation in human osteosarcoma

“…In addition, 1,25D appears to activate a cytoplasmic or membrane-associated VDR that triggers rapid signaling pathways that involve kinase activation and regulate cellular functions that prime the cell for latter 1,25D/VDR modulated response at the genomic level (10;11). In osteoblasts, cytoplasmic 1,25D signaling initiates nongenomic pathways via a classic VDR that include modulation of the electrical state of the plasma membrane (12)(13)(14), elevation of intracellular calcium (15), and activation of protein kinases including MAPKs (11). A crosstalk between 1,25D nongenomic and genomic actions leading to control of the cell cycle has been suggested at the point of MAPK activation in some cell types (16;17).…”