Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Invited Review
  • Published:

Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology

Abstract

A compromised vitamin D status, characterized by low 25-hydroxyvitamin D (25-(OH)D) serum levels, and a nutritional calcium deficit are widely encountered in European and North American countries, independent of age or gender. Both conditions are linked to the pathogenesis of many degenerative, malignant, inflammatory and metabolic diseases. Studies on tissue-specific expression and activity of vitamin D metabolizing enzymes, 25-(OH)D-1α-hydroxylase and 25-(OH)D-24-hydroxylase, and of the extracellular calcium-sensing receptor (CaR) have led to the understanding of how, in non-renal tissues and cellular systems, locally produced 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and extracellular Ca2+ act jointly as key regulators of cellular proliferation, differentiation and function. Impairment of cooperative signalling from the 1,25-(OH)2D3-activated vitamin D receptor (VDR) and from the CaR in vitamin D and calcium insufficiency causes cellular dysfunction in many organs and biological systems, and, therefore, increases the risk of diseases, particularly of osteoporosis, colorectal and breast cancer, inflammatory bowel disease, insulin-dependent diabetes mellitus type I, metabolic syndrome, diabetes mellitus type II, hypertension and cardiovascular disease. Understanding the underlying molecular and cellular processes provides a rationale for advocating adequate intake of vitamin D and calcium in all populations, thereby preventing many chronic diseases worldwide.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Adams JS, Hewison M (2008). Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 4, 80–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Almquist M, Manjer J, Bondeson L, Bondeson AG (2007). Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women. Cancer Causes Control 18, 595–602.

    Article  PubMed  Google Scholar 

  • Anderson PH, O’Loughlin PD, May BK, Morris HA (2005). Modulation of CYP27B1 and CYP24 mRNA expression in bone is independent of circulating 1,25(OH)(2)D(3) levels. Bone 36, 654–662.

    Article  CAS  PubMed  Google Scholar 

  • Armbrecht HJ, Hodam TL, Boltz MA, Kumar VB (1999). Capacity of a low calcium diet to induce the renal vitamin D 1a-hydroxylase is decreased in adult rats. Biochem Biophys Res Commun 255, 731–734.

    Article  CAS  PubMed  Google Scholar 

  • Atkins GJ, Anderson PH, Findlay DM, Welldon KJ, Vincent C, Zannettino AC et al. (2007). Metabolism of vitamin D3 in human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25-dihydroxyvitamin D3. Bone 40, 1517–1528.

    Article  CAS  PubMed  Google Scholar 

  • Bertone-Johnson ER, Chen WY, Holick MF, Hollis BW, Colditz GA, Willett WC et al. (2005). Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 14, 1991–1997.

    Article  CAS  PubMed  Google Scholar 

  • Berube S, Diorio C, Masse B, Hebert-Croteau N, Byrne C, Cote G et al. (2005). Vitamin D and calcium intakes from food or supplements and mammographic breast density. Cancer Epidemiol Biomarkers Prev 14, 1653–1659.

    Article  CAS  PubMed  Google Scholar 

  • Bilderback TR, Lee F, Auersperg N, Rodland KD (2002). Phosphatidylinositol 3-kinase-dependent, MEK- independent proliferation in response to CaR activation. Am J Physiol Cell Physiol 283, C282–C288.

    Article  CAS  PubMed  Google Scholar 

  • Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B (2006a). Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84, 18–28.

    Article  CAS  PubMed  Google Scholar 

  • Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B (2006b). Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: a 3-year randomized controlled trial. Arch Intern Med 166, 424–430.

    CAS  PubMed  Google Scholar 

  • Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P (2007). Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 92, 1415–1423.

    Article  CAS  PubMed  Google Scholar 

  • Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR (1999). Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol 149, 151–161.

    Article  CAS  PubMed  Google Scholar 

  • Brown EM, Lian JB (2008). New insights in bone biology: unmasking skeletal effects of the extracellular calcium-sensing receptor. Sci Signal 1, pe40.

    Article  PubMed  CAS  Google Scholar 

  • Canaff L, Hendy GN (2002). Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem 277, 30337–30350.

    Article  CAS  PubMed  Google Scholar 

  • Canaff L, Petit JL, Kisiel M, Watson PH, Gascon-Barre M, Hendy GN (2001). Extracellular calcium-sensing receptor is expressed in rat hepatocytes. Coupling to intracellular calcium mobilization and stimulation of bile flow. J Biol Chem 276, 4070–4079.

    Article  CAS  PubMed  Google Scholar 

  • Capiod T, Shuba Y, Skryma R, Prevarskaya N (2007). Calcium signalling and cancer cell growth. Subcell Biochem 45, 405–427.

    Article  CAS  PubMed  Google Scholar 

  • Chakrabarty S, Wang H, Canaff L, Hendy GN, Appelman H, Varani J (2005). Calcium sensing receptor in human colon carcinoma: interaction with Ca(2+) and 1,25-dihydroxyvitamin D(3). Cancer Res 65, 493–498.

    CAS  PubMed  Google Scholar 

  • Chang W, Tu C, Chen TH, Bikle D, Shoback D (2008). The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal 1, ra1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S et al. (1992). Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 327, 1637–1642.

    Article  CAS  PubMed  Google Scholar 

  • Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S et al. (1997). Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7, 439–443.

    Article  CAS  PubMed  Google Scholar 

  • Cheng I, Klingensmith ME, Chattopadhyay N, Kifor O, Butters RR, Soybel DI et al. (1998). Identification and localization of the extracellular calcium-sensing receptor in human breast. J Clin Endocrinol Metab 83, 703–707.

    CAS  PubMed  Google Scholar 

  • Cho E, Smith-Warner SA, Spiegelman D, Beeson WL, van den Brandt PA, Colditz GA et al. (2004). Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst 96, 1015–1022.

    Article  CAS  PubMed  Google Scholar 

  • Cifuentes M, Albala C, Rojas C (2005). Calcium-sensing receptor expression in human adipocytes. Endocrinology 146, 2176–2179.

    Article  CAS  PubMed  Google Scholar 

  • Colston KW, Hansen CM (2002). Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer. Endocr Relat Cancer 9, 45–59.

    Article  CAS  PubMed  Google Scholar 

  • Cross HS, Kallay E (2009). Regulation of the colonic vitamin D system for prevention of tumor progression: an update. Future Oncol 5, 493–507.

    Article  CAS  PubMed  Google Scholar 

  • Cross HS, Peterlik M, Reddy GS, Schuster I (1997). Vitamin D metabolism in human colon adenocarcinoma-derived Caco-2 cells: expression of 25-hydroxyvitamin D3-1alpha-hydroxylase activity and regulation of side-chain metabolism. J Steroid Biochem Mol Biol 62, 21–28.

    Article  CAS  PubMed  Google Scholar 

  • Davies KM, Heaney RP, Recker RR, Lappe JM, Barger-Lux MJ, Rafferty K et al. (2000). Calcium intake and body weight. J Clin Endocrinol Metab 85, 4635–4638.

    CAS  PubMed  Google Scholar 

  • Deeb KK, Trump DL, Johnson CS (2007). Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7, 684–700.

    Article  CAS  PubMed  Google Scholar 

  • Dobnig H, Pfeifer M, Begerow B, Suppan K (2005). Calcium, not vitamin D decreases blood pressure effectively in elderly subjects with low vitamin D levels; a randomized, double-blind, multi-center study. Abstracts of Annual Meeting of American Endocrine Society; 2005; San Diego, CA.

  • Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B et al. (2008). Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med 168, 1340–1349.

    Article  CAS  PubMed  Google Scholar 

  • Dong LM, Ulrich CM, Hsu L, Duggan DJ, Benitez DS, White E et al. (2008). Genetic variation in calcium-sensing receptor and risk for colon cancer. Cancer Epidemiol Biomarkers Prev 17, 2755–2765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dvorak MM, Siddiqua A, Ward DT, Carter DH, Dallas SL, Nemeth EF et al. (2004). Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci USA 101, 5140–5145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El Hiani Y, Ahidouch A, Roudbaraki M, Guenin S, Brule G, Ouadid-Ahidouch H (2006). Calcium-sensing receptor stimulation induces nonselective cation channel activation in breast cancer cells. J Membr Biol 211, 127–137.

    Article  CAS  PubMed  Google Scholar 

  • Equils O, Naiki Y, Shapiro AM, Michelsen K, Lu D, Adams J et al. (2006). 1,25-Dihydroxyvitamin D inhibits lipopolysaccharide-induced immune activation in human endothelial cells. Clin Exp Immunol 143, 58–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ (2005). Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 29, 21–30.

    Article  CAS  PubMed  Google Scholar 

  • Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW et al. (2004). Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 13, 1502–1508.

    CAS  PubMed  Google Scholar 

  • Forman JP, Bischoff-Ferrari HA, Willett WC, Stampfer MJ, Curhan GC (2005). Vitamin D intake and risk of incident hypertension: results from three large prospective cohort studies. Hypertension 46, 676–682.

    Article  CAS  PubMed  Google Scholar 

  • Froicu M, Weaver V, Wynn TA, McDowell MA, Welsh JE, Cantorna MT (2003). A crucial role for the vitamin d receptor in experimental inflammatory bowel diseases. Mol Endocrinol 17, 2386–2392.

    Article  CAS  PubMed  Google Scholar 

  • Giarratana N, Penna G, Amuchastegui S, Mariani R, Daniel KC, Adorini L (2004). A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development. J Immunol 173, 2280–2287.

    Article  CAS  PubMed  Google Scholar 

  • Grant WB, Garland CF (2006). The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res 26, 2687–2699.

    CAS  PubMed  Google Scholar 

  • Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Engelke JA, Shafer MM (2008). Vitamin D insufficiency: disease or no disease? J Bone Miner Res 23, 1052–1060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P et al. (2007). Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 103, 316–321.

    Article  CAS  PubMed  Google Scholar 

  • Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG et al. (2003). Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 170, 5382–5390.

    Article  CAS  PubMed  Google Scholar 

  • Hildebolt CF (2005). Effect of vitamin D and calcium on periodontitis. J Periodontol 76, 1576–1587.

    Article  CAS  PubMed  Google Scholar 

  • Huncharek M, Muscat J, Kupelnick B (2008). Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60, 421–441.

    Article  PubMed  Google Scholar 

  • Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM (2001). Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 1500–1503.

    Article  CAS  PubMed  Google Scholar 

  • Hypponen E, Power C (2007). Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 85, 860–868.

    Article  CAS  PubMed  Google Scholar 

  • Judd SE, Nanes MS, Ziegler TR, Wilson PW, Tangpricha V (2008). Optimal vitamin D status attenuates the age-associated increase in systolic blood pressure in white Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr 87, 136–141.

    Article  CAS  PubMed  Google Scholar 

  • Kallay E, Bises G, Bajna E, Bieglmayer C, Gerdenitsch W, Steffan I et al. (2005). Colon-specific regulation of vitamin D hydroxylases--a possible approach for tumor prevention. Carcinogenesis 26, 1581–1589.

    Article  CAS  PubMed  Google Scholar 

  • Kallay E, Bonner E, Wrba F, Thakker RV, Peterlik M, Cross HS (2003). Molecular and functional characterization of the extracellular calcium-sensing receptor in human colon cancer cells. Oncol Res 13, 551–559.

    Article  PubMed  Google Scholar 

  • Kallay E, Kifor O, Chattopadhyay N, Brown EM, Bischof MG, Peterlik M et al. (1997). Calcium-dependent c-myc proto-oncogene expression and proliferation of Caco-2 cells: a role for a luminal extracellular calcium-sensing receptor. Biochem Biophys Res Commun 232, 80–83.

    Article  CAS  PubMed  Google Scholar 

  • Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K et al. (2001). Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage. Carcinogenesis 22, 1429–1435.

    Article  CAS  PubMed  Google Scholar 

  • Krall EA, Wehler C, Garcia RI, Harris SS, Dawson-Hughes B (2001). Calcium and vitamin D supplements reduce tooth loss in the elderly. Am J Med 111, 452–456.

    Article  CAS  PubMed  Google Scholar 

  • Kudlacek S, Schneider B, Peterlik M, Leb G, Klaushofer K, Weber K et al. (2003). Assessment of vitamin D and calcium status in healthy adult Austrians. Eur J Clin Invest 33, 323–331.

    Article  CAS  PubMed  Google Scholar 

  • Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP (2007). Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85, 1586–1591.

    Article  CAS  PubMed  Google Scholar 

  • Lechner D, Kallay E, Cross HS (2007). 1alpha,25dihydroxyvitamin D3 downregulates CYP27B1 and induces CYP24A1 in colon cells. Mol Cell Endocrinol 263, 55–64.

    Article  CAS  PubMed  Google Scholar 

  • Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM (2007). Intakes of calcium and vitamin d and breast cancer risk in women. Arch Intern Med 167, 1050–1059.

    Article  CAS  PubMed  Google Scholar 

  • Lin KI, Chattopadhyay N, Bai M, Alvarez R, Dang CV, Baraban JM et al. (1998). Elevated extracellular calcium can prevent apoptosis via the calcium-sensing receptor. Biochem Biophys Res Commun 249, 325–331.

    Article  CAS  PubMed  Google Scholar 

  • Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR et al. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773.

    Article  CAS  PubMed  Google Scholar 

  • Looker AC, Mussolino ME (2008). Serum 25-hydroxyvitamin D and hip fracture risk in older U.S. White adults. J Bone Miner Res 23, 143–150.

    Article  CAS  PubMed  Google Scholar 

  • Loser K, Mehling A, Loeser S, Apelt J, Kuhn A, Grabbe S et al. (2006). Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med 12, 1372–1379.

    Article  CAS  PubMed  Google Scholar 

  • MacLeod RJ, Hayes M, Pacheco I (2007). Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells. Am J Physiol Gastrointest Liver Physiol 293, G403–G411.

    Article  CAS  PubMed  Google Scholar 

  • Martineau AR, Wilkinson KA, Newton SM, Floto RA, Norman AW, Skolimowska K et al. (2007). IFN-{gamma}- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin ll-37. J Immunol 178, 7190–7198.

    Article  CAS  PubMed  Google Scholar 

  • Mathiasen IS, Sergeev IN, Bastholm L, Elling F, Norman AW, Jaattela M (2002). Calcium and calpain as key mediators of apoptosis-like death induced by vitamin D compounds in breast cancer cells. J Biol Chem 277, 30738–30745.

    Article  CAS  PubMed  Google Scholar 

  • Mathieu C, Badenhoop K (2005). Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab 16, 261–266.

    Article  CAS  PubMed  Google Scholar 

  • Mathieu C, Van Etten E, Gysemans C, Decallonne B, Kato S, Laureys J et al. (2001). In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J Bone Miner Res 16, 2057–2065.

    Article  CAS  PubMed  Google Scholar 

  • McCarron DA, Reusser ME (1999). Finding consensus in the dietary calcium-blood pressure debate. J Am Coll Nutr 18, 398S–405S.

    Article  CAS  PubMed  Google Scholar 

  • Molostvov G, James S, Fletcher S, Bennett J, Lehnert H, Bland R et al. (2007). Extracellular calcium-sensing receptor is functionally expressed in human artery. Am J Physiol Renal Physiol 293, F946–F955.

    Article  CAS  PubMed  Google Scholar 

  • Negrea LA, Slatopolsky E, Dusso AS (1995). 1,25-Dihydroxyvitamin D synthesis in rat liver microsomes. Horm Metab Res 27, 461–464.

    Article  CAS  PubMed  Google Scholar 

  • Nittke T, Selig S, Kallay E, Cross HS (2008). Nutritional calcium modulates colonic expression of vitamin D receptor and pregnane X receptor target genes. Mol Nutr Food Res 52, 45–51.

    Google Scholar 

  • Olszak IT, Poznansky MC, Evans RH, Olson D, Kos C, Pollak MR et al. (2000). Extracellular calcium elicits a chemokinetic response from monocytes in vitro and in vivo. J Clin Invest 105, 1299–1305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Owen TA, Aronow MS, Barone LM, Bettencourt B, Stein GS, Lian JB (1991). Pleiotropic effects of vitamin D on osteoblast gene expression are related to the proliferative and differentiated state of the bone cell phenotype: dependency upon basal levels of gene expression, duration of exposure, and bone matrix competency in normal rat osteoblast cultures. Endocrinology 128, 1496–1504.

    Article  CAS  PubMed  Google Scholar 

  • Peterlik M, Cross HS (2005). Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 35, 290–304.

    Article  CAS  PubMed  Google Scholar 

  • Peters U, Chatterjee N, Yeager M, Chanock SJ, Schoen RE, McGlynn KA et al. (2004). Association of genetic variants in the calcium-sensing receptor with risk of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 13, 2181–2186.

    CAS  PubMed  Google Scholar 

  • Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner-Pammer A, Dobnig H (2009). Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int 20, 315–322.

    Article  CAS  PubMed  Google Scholar 

  • Pilz S, Dobnig H, Winklhofer-Roob B, Riedmuller G, Fischer JE, Seelhorst U et al. (2008). Low serum levels of 25-hydroxyvitamin D predict fatal cancer in patients referred to coronary angiography. Cancer Epidemiol Biomarkers Prev 17, 1228–1233.

    Article  CAS  PubMed  Google Scholar 

  • Pittas AG, Lau J, Hu FB, Dawson-Hughes B (2007). The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92, 2017–2029.

    Article  CAS  PubMed  Google Scholar 

  • Prineas RJ, Folsom AR, Zhang ZM, Sellers TA, Potter J (1997). Nutrition and other risk factors for renal cell carcinoma in postmenopausal women. Epidemiology 8, 31–36.

    Article  CAS  PubMed  Google Scholar 

  • Ritter CS, Armbrecht HJ, Slatopolsky E, Brown AJ (2006). 25-Hydroxyvitamin D(3) suppresses PTH synthesis and secretion by bovine parathyroid cells. Kidney Int 70, 654–659.

    Article  CAS  PubMed  Google Scholar 

  • Rodland KD (2004). The role of the calcium-sensing receptor in cancer. Cell Calcium 35, 291–295.

    Article  CAS  PubMed  Google Scholar 

  • Rowling MJ, Kemmis CM, Taffany DA, Welsh J (2006). Megalin-mediated endocytosis of vitamin d binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr 136, 2754–2759.

    Article  CAS  PubMed  Google Scholar 

  • Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D et al. (2007). Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 117, 803–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spach KM, Nashold FE, Dittel BN, Hayes CE (2006). IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol 177, 6030–6037.

    Article  CAS  PubMed  Google Scholar 

  • Squires PE, Harris TE, Persaud SJ, Curtis SB, Buchan AM, Jones PM (2000). The extracellular calcium-sensing receptor on human beta-cells negatively modulates insulin secretion. Diabetes 49, 409–417.

    Article  CAS  PubMed  Google Scholar 

  • Tfelt-Hansen J, Brown EM (2005). The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 42, 35–70.

    Article  CAS  PubMed  Google Scholar 

  • Tfelt-Hansen J, Hansen JL, Smajilovic S, Terwilliger EF, Haunso S, Sheikh SP (2006). Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes. Am J Physiol Heart Circ Physiol 290, H1165–H1171.

    Article  CAS  PubMed  Google Scholar 

  • Tfelt-Hansen J, Yano S, John Macleod R, Smajilovic S, Chattopadhyay N, Brown EM (2005). High calcium activates the EGF receptor potentially through the calcium-sensing receptor in Leydig cancer cells. Growth Factors 23, 117–123.

    Article  CAS  PubMed  Google Scholar 

  • Thien R, Baier K, Pietschmann P, Peterlik M, Willheim M (2005). Interactions of 1 alpha,25-dihydroxyvitamin D3 with IL-12 and IL-4 on cytokine expression of human T lymphocytes. J Allergy Clin Immunol 116, 683–689.

    Article  CAS  PubMed  Google Scholar 

  • Tuohimaa P, Tenkanen L, Ahonen M, Lumme S, Jellum E, Hallmans G et al. (2004). Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 108, 104–108.

    Article  CAS  PubMed  Google Scholar 

  • van Driel M, Koedam M, Buurman CJ, Hewison M, Chiba H, Uitterlinden AG et al. (2006). Evidence for auto/paracrine actions of vitamin D in bone: 1alpha-hydroxylase expression and activity in human bone cells. FASEB J 20, 2417–2419.

    Article  CAS  PubMed  Google Scholar 

  • Wang D, An SJ, Wang WH, McGiff JC, Ferreri NR (2001). CaR-mediated COX-2 expression in primary cultured mTAL cells. Am J Physiol Renal Physiol 281, F658–F664.

    Article  CAS  PubMed  Google Scholar 

  • Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K et al. (2008). Vitamin D deficiency and risk of cardiovascular disease. Circulation 117, 503–511.

    Article  CAS  PubMed  Google Scholar 

  • Wiers K, Wright MA, Vellody K, Young MR (1998). Failure of tumor-reactive lymph node cells to kill tumor in the presence of immune-suppressive CD34+ cells can be overcome with vitamin D3 treatment to diminish CD34+ cell levels. Clin Exp Metastasis 16, 275–282.

    Article  CAS  PubMed  Google Scholar 

  • Wu-Wong JR, Nakane M, Ma J, Ruan X, Kroeger PE (2006). Effects of vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis 186, 20–28.

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Garami M, Cheng T, Gardner DG (1996). 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Invest 97, 1577–1588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi T, Chattopadhyay N, Kifor O, Butters Jr RR, Sugimoto T, Brown EM (1998a). Mouse osteoblastic cell line (MC3T3-E1) expresses extracellular calcium (Ca2+o)-sensing receptor and its agonists stimulate chemotaxis and proliferation of MC3T3-E1 cells. J Bone Miner Res 13, 1530–1538.

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi T, Olozak I, Chattopadhyay N, Butters RR, Kifor O, Scadden DT et al. (1998b). Expression of extracellular calcium (Ca2+o)-sensing receptor in human peripheral blood monocytes. Biochem Biophys Res Commun 246, 501–506.

    Article  CAS  PubMed  Google Scholar 

  • Yano S, Brown EM, Chattopadhyay N (2004a). Calcium-sensing receptor in the brain. Cell Calcium 35, 257–264.

    Article  CAS  PubMed  Google Scholar 

  • Yano S, Macleod RJ, Chattopadhyay N, Tfelt-Hansen J, Kifor O, Butters RR et al. (2004b). Calcium-sensing receptor activation stimulates parathyroid hormone-related protein secretion in prostate cancer cells: role of epidermal growth factor receptor transactivation. Bone 35, 664–672.

    Article  CAS  PubMed  Google Scholar 

  • Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM et al. (2001). Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86, 888–894.

    CAS  PubMed  Google Scholar 

  • Zhu Y, Mahon BD, Froicu M, Cantorna MT (2005). Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol 35, 217–224.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Felix Bronner, Professor emeritus at the University of Connecticut Health Center at Farmington (USA), for critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Peterlik.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peterlik, M., Cross, H. Vitamin D and calcium insufficiency-related chronic diseases: molecular and cellular pathophysiology. Eur J Clin Nutr 63, 1377–1386 (2009). https://doi.org/10.1038/ejcn.2009.105

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2009.105

Keywords

This article is cited by

Search

Quick links