Calcium Nutrition and Extracellular Calcium Sensing: Relevance for the Pathogenesis of Osteoporosis, Cancer and Cardiovascular Diseases

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 Ca(2+) to function as a “first messenger” for various intracellular signaling cascades. Evidence demonstrates that Ca(2+)/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 Ca(2+) influx into breast cancer cells, thereby activating pro-apoptotic intracellular signaling. Furthermore, Ca(2+)/CaSR signaling opens Ca(2+)-sensitive K(+) conductance channels in vascular endothelial cells, and also participates in IP(3)-dependent regulation of cytoplasmic Ca(2+), the key intermediate of cardiomyocyte functions. Consequently, impairment of Ca(2+)/CaSR signaling may contribute to inadequate bone formation, tumor progression, hypertension, vascular calcification and, probably, cardiovascular disease.