Calcium nutrition and extracellular calcium sensing: relevance for the pathogenesis of osteoporosis, cancer and cardiovascular diseases

Abstract

Through a systematic search in Pubmed for literature, on links between calcium malnutrition and risk of chronic diseases, we found the highest degree of evidence for osteoporosis, colorectal and breast cancer, as well as for hypertension, as the only major cardiovascular risk factor. Low calcium intake apparently has some impact also on cardiovascular events and disease outcome. Calcium malnutrition can causally be related to low activity of the extracellular calcium-sensing receptor (CaSR). This member of the family of 7-TM G-protein coupled receptors allows extracellular Ca2+ to function as a "first messenger" for various intracellular signaling cascades. Evidence demonstrates that Ca2+/CaSR signaling in functional linkage with vitamin D receptor (VDR)-activated pathways (i) promotes osteoblast differentiation and formation of mineralized bone; (ii) targets downstream effectors of the canonical and non-canonical Wnt pathway to inhibit proliferation and induce differentiation of colorectal cancer cells; (iii) evokes Ca2+ influx into breast cancer cells, thereby activating pro-apoptotic intracellular signaling. Furthermore, Ca2+/CaSR signaling opens Ca2+-sensitive K+ conductance channels in vascular endothelial cells, and also participates in IP(3)-dependent regulation of cytoplasmic Ca2+, the key intermediate of cardiomyocyte functions. Consequently, impairment of Ca2+/CaSR signaling may contribute to inadequate bone formation, tumor progression, hypertension, vascular calcification and, probably, cardiovascular disease.

Figure 1

The extracellular calcium-sensing receptor (CaSR) senses, amplifies and transduces minute variations in [Ca²⁺]_o into various intracellular signaling pathways. Bold arrows indicate coupling to stimulatory G proteins, dotted arrows indicate coupling to inhibitory G proteins. Only cell-specific pathways relevant for the diseases mentioned in the text are shown (for more details on CaSR-activated pathways, see Magno et al. [119]).

Figure 2

Cooperative signaling from Ca²⁺/CaSR and 1,25-(OH)₂D₃/VDR on Wnt pathways and formation of mineralized bone.

Figure 3

Cooperative signaling from Ca²⁺/CaSR and 1,25-(OH)₂D₃/VDR on Wnt pathways inhibits proliferation and promotes differentiation of colonocytes and of colorectal cancer cells.