- Email: [email protected]
Highlights from the 18th workshop on vitamin D, Delft, The Netherlands, April 21–24, 2015
Journal of Steroid Biochemistry & Molecular Biology 164 (2016) 1–3
Contents lists available at ScienceDirect
Journal of Steroid Biochemistry & Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb
Editorial
Highlights from the 18th workshop on vitamin D, Delft, The Netherlands, April 21–24, 2015
The 18th vitamin D workshop was organized in Delft, the city of the painter Johannes Vermeer. Delft was chosen because of its proximity to Rotterdam, the venue of the European Calcified Tissue Symposium, April 25–28, 2015. Delft is a small medieval city with a lot of character and hotels, restaurants and historical sites within walking distance of the Workshop venue, the Theater de Veste. The Workshop was attended by 340 investigators, clinicians, basic scientists and epidemiologists. The organizers were Dr Paul Lips (Chair), Dr JoEllen Welsh (Past Chair), Dr Roger Bouillon, Dr Renate de Jongh and Dr Natasja van Schoor (Local Committee Members) with the assistance of Inge van Marion and Lucienne Dado (Ab Initio) and Roxanne Hall (Meetings Plus). During the three days of the Workshop, 20 invited lectures, 30 free oral communications and 168 posters were presented. The Organizing Committee was assisted by the Workshop Executive Committee and the Program Advisory Committee who contributed to the development of the program, the ranking of the abstracts and manuscript peer review for this special issue. The committee members are listed on the Workshop’s website at www.vitamindworkshop.org. All delegates who presented at the Workshop were invited to prepare a manuscript for this special issue of the Journal of Steroid Biochemistry and Molecular Biology. The manuscripts include reviews by the invited speakers and research papers by all other presenters. All manuscripts were peer reviewed by at least two reviewers according to the standard of the Journal. Guest Editors were Drs Lips, Welsh, Bouillon and Demay. The Guest Editors would like to acknowledge the assistance of Dr Jerzy Adamski and the Elsevier support staff who helped to prepare this Special Issue. We thank the many reviewers who assisted in the reviewing of the manuscripts. The following paragraphs summarize the sessions of the Workshop, highlighting the invited speaker presentations. The fourteen sessions of the Workshop covered the new developments in the different aspects of vitamin D research, including, basic, clinical and epidemiological studies. The first day started with the opening remarks by the chair, followed by the first session on Molecular Genetics and Vitamin D Action. Dr Andre´ Uitterlinden (Erasmus Medical Center, Rotterdam) gave an excellent overview on the discovery of the genes involved in height, osteoporosis, vitamin D and osteoarthritis. Genome-wide association studies (GWAS) have been highly successful in the discovery of DNA-variants that affect these parameters. The effect per gene variant usually is modest and the explained variance for height is about 25% and for BMD ranges http://dx.doi.org/10.1016/j.jsbmb.2016.10.005 0960-0760/ß 2016 Published by Elsevier Ltd.
from 3 to 7%. Translation into pathophysiology takes more time. While GWAS assesses less than 1% of the human genome, next generation sequencing and exome arrays assess all coding parts of the human genome. Very large consortia are needed. Next, Dr Roger Bouillon (Katholieke Universiteit Leuven, Belgium) gave an update on the vitamin D binding protein (DBP) or group-specific component (Gc), a highly polymorphic protein with many variants worldwide. The variant Gc-1f is common in tropical regions while Gc-1s and Gc-2 are more common in northern regions. Whether the affinity of the protein for vitamin D metabolites varies with genotype is disputed. The assessment of DBP by monoclonal assay is incomplete, resulting in falsely lower concentrations with certain polymorphisms, commonly found in blacks. This may lead to erroneously calculated lower concentrations of free 25hydroxyvitamin D. The subject of the second session was Vitamin D metabolism and Calcium Absorption. Dr Vin Tangpricha (Emory University, Atlanta, Georgia) discussed vitamin D absorption in cystic fibrosis (CF) the most common life shortening genetic disease in North America. In CF the chloride transport is disrupted on epithelial surfaces of the lung, intestine, pancreas and reproductive tracts. The pancreatic ducts become obstructed leading to pancreatic insufficiency and decreased absorption of vitamin D. Investigations of his group suggest that high dose vitamin D therapy may help recovery from acute pulmonary infections and improve one-year survival following hospitalization for CF. The third session concentrated on Renal Physiology and Diseases. Dr Reinhold Erben (University of Veterinary Medicine, Vienna, Austria) discussed translational and clinical research on the interactions between vitamin D metabolites, FGF-23 and calcium channels. FGF-23 is a regulator of calcium channel TRPV5 in the renal distal tubule. It stimulates calcium and sodium reabsorption in the kidney. Dr Erben illustrated the pathophysiological importance of these mechanisms by the fact that mice with deletions of both FGF-23 and the vitamin D receptor are protected against renal disease progression, fluid retention, hypertension and left ventricular failure caused by experimental renal disease. Dr Marc Vervloet (VU University Medical Center, Amsterdam, The Netherlands) gave an overview of the role of FGF-23 and vitamin D in patients with chronic renal failure. While FGF-23 decreases 1,25(OH)2D formation, a negative feedback loop, other regulators of FGF-23 are calcium and phosphate concentrations, iron status, klotho and maybe bone mineralization and osteocyte health. FGF23 initially increases to compensate for phosphate retention, but in
2
Editorial / Journal of Steroid Biochemistry & Molecular Biology 164 (2016) 1–3
later stages of chronic kidney disease (CKD) the increase is exaggerated and inappropriate. FGF-23 is one of the most important predictors of cardiovascular events and mortality in CKD. New research suggests that FGF-23 is a marker of bone health in CKD. Renal bone disease as such may be linked to cardiovascular disease in CKD patients. The fourth session was on Vitamin D and Cancer. Dr Marjolein van Driel (Erasmus Medical Center, Rotterdam, the Netherlands) gave an account of her research on the effect of vitamin D metabolites in models of bone metastasis. She studied the crosstalk between osteoblasts and metastatic cancer cells in a co-culture model of differentiating human osteoblasts and metastatic prostate cancer cells. Early osteoblasts stimulated but later osteoblasts (in the mineralization stage) inhibited growth of metastatic prostate cancer cells. The prostate cancer cells in turn kept the osteoblasts in an early differentiation stage. The active vitamin D metabolite 1,25(OH)2D stimulated osteoblast differentiation and inhibited prostate cancer cell growth. The Measurement of Vitamin D Metabolites was the subject of the fifth session. Dr Glenville Jones discussed the metabolic profile of vitamin D metabolites as measured simultaneously by liquid chromatography-tandem mass spectrometry (LC–MS/MS). This approach was used by Dr Jones to study genetic defects in humans and the consequences of ablation of the CYP2R1, CYP 27A, CYP27B, CYP24A1 and VDR genes in mice. Loss of CYP24A1 resulted in absence of 24,25(OH)2D and 25(OH)D-26,23-lactone. The ratio of 25(OH)D/24,25(OH)2D measured simultaneously, is a screening test for loss-of-function mutations of CYP24A1, resulting in infantile hypercalcemia and renal stones in children and adults. Dr Chris Sempos (National Institute of Health, Washington, USA) discussed the important subject of standardization of vitamin D assays. Assay variation confounds clinical diagnosis of vitamin D deficiency and pooling of data. The Vitamin D Standardization Program (VDSP) was developed to overcome these problems by reference measurement procedures and providing standard reference materials. The second day started with two sessions VI and VII sponsored by the World Health Organization. The sessions were introduced by Dr Juan Pablo Pena˜-Rosas (WHO, Gene`ve, Switzerland). He illustrated how the WHO programs are designed and implemented. Session VI on Prevalence, Diagnosis and Prevention of Rickets included Dr John Pettifor (University of the Witwatersrand, Johannesburg, South Africa) on the screening of communities for vitamin D deficiency rickets. He discussed the clinical picture and radiological confirmation of the diagnosis of rickets. The presence of rachitic deformities has been proposed as a screening tool, but only one third has been confirmed by radiographs. Alkaline phosphatase has also been proposed, but false positives are possible. Serum 25(OH)D is not a screening test, because it does not indicate active rickets or rickets caused by low calcium intake. Urine phosphate and sebacic acid have recently been proposed as screening tests but these need to be confirmed. The second presentation on the prevention and treatment of rickets and the recommendations on vitamin D was given by Dr Nick Shaw (Birmingham Children’s Hospital, UK). The incidence of rickets in the UK has been increasing in recent years. Rickets is due to vitamin D deficiency and/or low calcium intake. Dr Shaw reported on the international consensus meeting organized by the European Society of Paediatric Endocrinology. Pregnant women and their children should receive vitamin D supplementation. Evidence from randomized clinical trials shows that infants who receive vitamin D 400 IU per day achieve a serum 25(OH)D above 50 nmol/l. It is a challenge to implement daily supplementation. Food fortification strategies need to be revisited to improve vitamin D status in the population. Nutritional rickets is treated with daily oral vitamin D and calcium. Session VII was on Vitamin D Deficiency during Pregnancy. Dr Cristina Palacios (Graduate School of Public Health,
University of Puerto Rico) discussed the issue of whether vitamin D supplements should be given during pregnancy. During pregnancy, serum 1,25(OH)2D increases gradually, depending on adequate serum 25(OH)D levels. Vitamin D deficiency in pregnancy has been associated with pre-eclampsia, gestational diabetes, preterm birth and low birth weight. She performed a Cochrane meta-analysis on the effect of vitamin D in clinical trials during pregnancy. Vitamin D supplementation increases serum 25(OH)D at term. Some trials suggested that the risk for low birth weight decreased with vitamin D, but evidence on other outcomes was lacking. The second presentation on maternal vitamin D status and risk of preeclampsia was given by Dr Marjan Tabesh (Isfahan University of Medical Sciences, Iran), who reported a systematic review and meta-analysis on the subject. The meta-analysis on 8 relevant papers showed a significant association between vitamin D deficiency and the risk of pre-eclampsia. The third presentation by Dr Cyrus Cooper (University of Southampton and University of Oxford, UK) was on maternal vitamin D status and pre- and postnatal bone development in the child. Fracture risk may be modified by environmental influences during intra-uterine or the first year of life. Epidemiological studies show a relationship between low birth weight and/or stunted growth in the first year with lower bone mineral density, an altered setting of the vitamin D-PTH axis, and an increased risk of hip fracture in later life. A recent clinical trial showed that vitamin D supplementation in pregnancy resulted in a higher bone mineral density at 4 years of age compared to placebo in children born during wintertime. These presentations were followed by a WHO Round Table Discussion on Translating Research into Evidenceinformed Policy Options to Address Vitamin D Nutrition chaired by Dr Roger Bouillon and Dr Inez Schoenmakers (Oxford, UK). Short introductions were given by Dr Peˆna-Rosas, Dr ChrisTel.: Lamberg Allardt Helsinki, Finland and Dr John Pettifor Session VIII had as subject Vitamin D Nutrition and Supplementation. Dr Mairead Kiely (University College Cork, Ireland) gave a presentation on modelling of vitamin D intake and effects of food fortification. Currently dietary intake does not meet the recommended vitamin D intake and food fortification could be an effective method to increase vitamin D intake over the whole population with minimal risk for excessive dosing. Well-designed and sustainable fortification can be achieved by modeling usual food consumption intakes in representative populations. The effects of modelling of vitamin D intake and food fortification on vitamin D status were shown. Session IX had as subject Vitamin D and Immunology. Dr Chantal Mathieu (Catholic University, Leuven, Belgium) gave an overview of the relationship between vitamin D and type 1 diabetes. The antigen presenting dendritic cell plays a central role in the effect of 1,25(OH)2D on the immune system. This metabolite also induces the generation of regulator T-cells, and alters the cytokine profile of monocytes/macrophages. Transcriptome analysis showed an inhibitory effect of 1,25(OH)2D on islets of Langerhans, maybe contributing to decrease inflammation in early type 1 diabetes. The relationship between vitamin D and infectious diseases was discussed by Dr Adrian Martineau (London School of Medicine and Dentistry, Queen Mary University, London, UK). The active vitamin D metabolite stimulates the induction of protective immune responses to viral and bacterial infections. Epidemiologic studies show an association between vitamin D deficiency and susceptibility to infection and also adverse outcome. Numerous clinical trials investigate the effect of vitamin D on the number and clinical outcome of respiratory infections. Some of these show small effects on antibacterial proteins and the number of respiratory infections. Unfortunately, the Friday morning plenary lecture was cancelled due to an unanticipated issue of the keynote speaker.
Editorial / Journal of Steroid Biochemistry & Molecular Biology 164 (2016) 1–3
Therefore, the morning workshop started with Session XI on Vitamin D and its Receptor: Molecular Mechanisms. The invited presentation was by Dr Mark Meyer (University of Wisconsin, Madison, USA) on dynamic VDR control of gene expression during differentiation and selective regulation of MMP13 transcription. Cell differentiation alters transcriptomic response to 1,25(OH)2D, with many genes no longer responsive, while others show an altered, often enhanced response. Matrix metalloprotease 13 (MMP13) shows a striking increased sensitivity to 125(OH)2D upon differentiation. The enhancing activity can be blocked by deletion of 3 areas upstream of the gene. The subject of session XII was Vitamin D, muscle and cardiovascular system. The first presentation was by Dr Ralph Brandes (Goethe University, Frankfurt, Germany) on vascular regeneration. A low dose of 1,25(OH)2D enhanced carotid artery re-endothelialization and increased the number of angiogenic myeloid cells. Arteries treated with 1,25(OH)2D had a chemotactic effect on angiogenic myeloid cells, which could be blocked by SDF1 antibodies. In healthy volunteers treatment with vitamin D3 4000 IU/d increased the number of angiogenic myeloid cells. In the second presentation Dr Heike Bischoff-Ferrari (University Hospital Zurich, Switzerland) discussed the effects of high-dose vitamin D supplementation on fall incidence in the elderly. International organizations and guidelines support vitamin D supplementation as an effective intervention to prevent falling in older people. A recent randomized clinical trial in Switzerland compared a high dose of vitamin D with a lower dose and with a combination of the lower dose and calcifediol (25(OH)D). Unexpectedly, the higher dose supplementation induced higher serum 25(OH)D levels but resulted in more falls than the lower dose control intervention. Session XIII had as subject Vitamin D and Bone. The invited speaker was Dr Paul Anderson (University of South Australia, Adelaide, Australia) who spoke on the local synthesis of 1a,25(OH)2D3 in vivo. While CYP27B1 regulates bone formation in osteoblasts in vitro, the importance of the local synthesis of 1,25(OH)2D for osteoblastic function in vivo is not clear. Osteoblast specific CYP27B1KO mice were reported to exhibit normal concentrations of 1,25(OH)2D, PTH, calcium, phosphate, but a 18% reduction of trabecular bone volume in the spine. The osteoblast specific CYP27B1 transgenic mice, however showed a
3
14% increase in vertebral trabecular bone volume and an increase of trabecular thickness. These experiments show that the local synthesis of 1,25(OH)2D promotes bone formation. The last session included selected oral presentations and late breaking news. We thank the generous sponsors of the 18th Vitamin D Workshop in Delft. The Workshop received a Conference Grant (R13AG048689) from the National Institute on Aging which funded invited speakers and Young Investigator and Trainee Travel Awards. Heartland Assays sponsored again as in previous years Trainee Travel Awards. The World Health Organization (Geneva, Switzerland) generously sponsored Sessions VI and VII, including the invited speakers. Corporate sponsors included Pfizer, Chugai Pharmaceutical Co, Biotech Pharmacal Inc, Tejin Pharma Ltd, DSM, Merck, Galephar, Diasource ImmunoAssays, Cerbios, Roche Diagnostics International, Fujirebio Europe, Elsevier, Friesland Campina. Paul Lips* Department of Internal Medicine, Endocrine Section, VU University Medical Center, P.O. Box 7057 Box 7057, 1007 MB, Amsterdam, The Netherlands JoEllen Welsh University at Albany Cancer Research Center, 1 Discovery Drive Suite 304D, Rensselaer, NY 12144, United States Marie Demay Endocrine Unit, Harvard Medical School, Boston, MA 02114, United States Roger Bouillon Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, B-3000, Leuven, Belgium *Corresponding author E-mail addresses: [email protected] (P. Lips), [email protected] (J. Welsh), [email protected] (M. Demay), [email protected] (R. Bouillon).
Contents lists available at ScienceDirect
Journal of Steroid Biochemistry & Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb
Editorial
Highlights from the 18th workshop on vitamin D, Delft, The Netherlands, April 21–24, 2015
The 18th vitamin D workshop was organized in Delft, the city of the painter Johannes Vermeer. Delft was chosen because of its proximity to Rotterdam, the venue of the European Calcified Tissue Symposium, April 25–28, 2015. Delft is a small medieval city with a lot of character and hotels, restaurants and historical sites within walking distance of the Workshop venue, the Theater de Veste. The Workshop was attended by 340 investigators, clinicians, basic scientists and epidemiologists. The organizers were Dr Paul Lips (Chair), Dr JoEllen Welsh (Past Chair), Dr Roger Bouillon, Dr Renate de Jongh and Dr Natasja van Schoor (Local Committee Members) with the assistance of Inge van Marion and Lucienne Dado (Ab Initio) and Roxanne Hall (Meetings Plus). During the three days of the Workshop, 20 invited lectures, 30 free oral communications and 168 posters were presented. The Organizing Committee was assisted by the Workshop Executive Committee and the Program Advisory Committee who contributed to the development of the program, the ranking of the abstracts and manuscript peer review for this special issue. The committee members are listed on the Workshop’s website at www.vitamindworkshop.org. All delegates who presented at the Workshop were invited to prepare a manuscript for this special issue of the Journal of Steroid Biochemistry and Molecular Biology. The manuscripts include reviews by the invited speakers and research papers by all other presenters. All manuscripts were peer reviewed by at least two reviewers according to the standard of the Journal. Guest Editors were Drs Lips, Welsh, Bouillon and Demay. The Guest Editors would like to acknowledge the assistance of Dr Jerzy Adamski and the Elsevier support staff who helped to prepare this Special Issue. We thank the many reviewers who assisted in the reviewing of the manuscripts. The following paragraphs summarize the sessions of the Workshop, highlighting the invited speaker presentations. The fourteen sessions of the Workshop covered the new developments in the different aspects of vitamin D research, including, basic, clinical and epidemiological studies. The first day started with the opening remarks by the chair, followed by the first session on Molecular Genetics and Vitamin D Action. Dr Andre´ Uitterlinden (Erasmus Medical Center, Rotterdam) gave an excellent overview on the discovery of the genes involved in height, osteoporosis, vitamin D and osteoarthritis. Genome-wide association studies (GWAS) have been highly successful in the discovery of DNA-variants that affect these parameters. The effect per gene variant usually is modest and the explained variance for height is about 25% and for BMD ranges http://dx.doi.org/10.1016/j.jsbmb.2016.10.005 0960-0760/ß 2016 Published by Elsevier Ltd.
from 3 to 7%. Translation into pathophysiology takes more time. While GWAS assesses less than 1% of the human genome, next generation sequencing and exome arrays assess all coding parts of the human genome. Very large consortia are needed. Next, Dr Roger Bouillon (Katholieke Universiteit Leuven, Belgium) gave an update on the vitamin D binding protein (DBP) or group-specific component (Gc), a highly polymorphic protein with many variants worldwide. The variant Gc-1f is common in tropical regions while Gc-1s and Gc-2 are more common in northern regions. Whether the affinity of the protein for vitamin D metabolites varies with genotype is disputed. The assessment of DBP by monoclonal assay is incomplete, resulting in falsely lower concentrations with certain polymorphisms, commonly found in blacks. This may lead to erroneously calculated lower concentrations of free 25hydroxyvitamin D. The subject of the second session was Vitamin D metabolism and Calcium Absorption. Dr Vin Tangpricha (Emory University, Atlanta, Georgia) discussed vitamin D absorption in cystic fibrosis (CF) the most common life shortening genetic disease in North America. In CF the chloride transport is disrupted on epithelial surfaces of the lung, intestine, pancreas and reproductive tracts. The pancreatic ducts become obstructed leading to pancreatic insufficiency and decreased absorption of vitamin D. Investigations of his group suggest that high dose vitamin D therapy may help recovery from acute pulmonary infections and improve one-year survival following hospitalization for CF. The third session concentrated on Renal Physiology and Diseases. Dr Reinhold Erben (University of Veterinary Medicine, Vienna, Austria) discussed translational and clinical research on the interactions between vitamin D metabolites, FGF-23 and calcium channels. FGF-23 is a regulator of calcium channel TRPV5 in the renal distal tubule. It stimulates calcium and sodium reabsorption in the kidney. Dr Erben illustrated the pathophysiological importance of these mechanisms by the fact that mice with deletions of both FGF-23 and the vitamin D receptor are protected against renal disease progression, fluid retention, hypertension and left ventricular failure caused by experimental renal disease. Dr Marc Vervloet (VU University Medical Center, Amsterdam, The Netherlands) gave an overview of the role of FGF-23 and vitamin D in patients with chronic renal failure. While FGF-23 decreases 1,25(OH)2D formation, a negative feedback loop, other regulators of FGF-23 are calcium and phosphate concentrations, iron status, klotho and maybe bone mineralization and osteocyte health. FGF23 initially increases to compensate for phosphate retention, but in
2
Editorial / Journal of Steroid Biochemistry & Molecular Biology 164 (2016) 1–3
later stages of chronic kidney disease (CKD) the increase is exaggerated and inappropriate. FGF-23 is one of the most important predictors of cardiovascular events and mortality in CKD. New research suggests that FGF-23 is a marker of bone health in CKD. Renal bone disease as such may be linked to cardiovascular disease in CKD patients. The fourth session was on Vitamin D and Cancer. Dr Marjolein van Driel (Erasmus Medical Center, Rotterdam, the Netherlands) gave an account of her research on the effect of vitamin D metabolites in models of bone metastasis. She studied the crosstalk between osteoblasts and metastatic cancer cells in a co-culture model of differentiating human osteoblasts and metastatic prostate cancer cells. Early osteoblasts stimulated but later osteoblasts (in the mineralization stage) inhibited growth of metastatic prostate cancer cells. The prostate cancer cells in turn kept the osteoblasts in an early differentiation stage. The active vitamin D metabolite 1,25(OH)2D stimulated osteoblast differentiation and inhibited prostate cancer cell growth. The Measurement of Vitamin D Metabolites was the subject of the fifth session. Dr Glenville Jones discussed the metabolic profile of vitamin D metabolites as measured simultaneously by liquid chromatography-tandem mass spectrometry (LC–MS/MS). This approach was used by Dr Jones to study genetic defects in humans and the consequences of ablation of the CYP2R1, CYP 27A, CYP27B, CYP24A1 and VDR genes in mice. Loss of CYP24A1 resulted in absence of 24,25(OH)2D and 25(OH)D-26,23-lactone. The ratio of 25(OH)D/24,25(OH)2D measured simultaneously, is a screening test for loss-of-function mutations of CYP24A1, resulting in infantile hypercalcemia and renal stones in children and adults. Dr Chris Sempos (National Institute of Health, Washington, USA) discussed the important subject of standardization of vitamin D assays. Assay variation confounds clinical diagnosis of vitamin D deficiency and pooling of data. The Vitamin D Standardization Program (VDSP) was developed to overcome these problems by reference measurement procedures and providing standard reference materials. The second day started with two sessions VI and VII sponsored by the World Health Organization. The sessions were introduced by Dr Juan Pablo Pena˜-Rosas (WHO, Gene`ve, Switzerland). He illustrated how the WHO programs are designed and implemented. Session VI on Prevalence, Diagnosis and Prevention of Rickets included Dr John Pettifor (University of the Witwatersrand, Johannesburg, South Africa) on the screening of communities for vitamin D deficiency rickets. He discussed the clinical picture and radiological confirmation of the diagnosis of rickets. The presence of rachitic deformities has been proposed as a screening tool, but only one third has been confirmed by radiographs. Alkaline phosphatase has also been proposed, but false positives are possible. Serum 25(OH)D is not a screening test, because it does not indicate active rickets or rickets caused by low calcium intake. Urine phosphate and sebacic acid have recently been proposed as screening tests but these need to be confirmed. The second presentation on the prevention and treatment of rickets and the recommendations on vitamin D was given by Dr Nick Shaw (Birmingham Children’s Hospital, UK). The incidence of rickets in the UK has been increasing in recent years. Rickets is due to vitamin D deficiency and/or low calcium intake. Dr Shaw reported on the international consensus meeting organized by the European Society of Paediatric Endocrinology. Pregnant women and their children should receive vitamin D supplementation. Evidence from randomized clinical trials shows that infants who receive vitamin D 400 IU per day achieve a serum 25(OH)D above 50 nmol/l. It is a challenge to implement daily supplementation. Food fortification strategies need to be revisited to improve vitamin D status in the population. Nutritional rickets is treated with daily oral vitamin D and calcium. Session VII was on Vitamin D Deficiency during Pregnancy. Dr Cristina Palacios (Graduate School of Public Health,
University of Puerto Rico) discussed the issue of whether vitamin D supplements should be given during pregnancy. During pregnancy, serum 1,25(OH)2D increases gradually, depending on adequate serum 25(OH)D levels. Vitamin D deficiency in pregnancy has been associated with pre-eclampsia, gestational diabetes, preterm birth and low birth weight. She performed a Cochrane meta-analysis on the effect of vitamin D in clinical trials during pregnancy. Vitamin D supplementation increases serum 25(OH)D at term. Some trials suggested that the risk for low birth weight decreased with vitamin D, but evidence on other outcomes was lacking. The second presentation on maternal vitamin D status and risk of preeclampsia was given by Dr Marjan Tabesh (Isfahan University of Medical Sciences, Iran), who reported a systematic review and meta-analysis on the subject. The meta-analysis on 8 relevant papers showed a significant association between vitamin D deficiency and the risk of pre-eclampsia. The third presentation by Dr Cyrus Cooper (University of Southampton and University of Oxford, UK) was on maternal vitamin D status and pre- and postnatal bone development in the child. Fracture risk may be modified by environmental influences during intra-uterine or the first year of life. Epidemiological studies show a relationship between low birth weight and/or stunted growth in the first year with lower bone mineral density, an altered setting of the vitamin D-PTH axis, and an increased risk of hip fracture in later life. A recent clinical trial showed that vitamin D supplementation in pregnancy resulted in a higher bone mineral density at 4 years of age compared to placebo in children born during wintertime. These presentations were followed by a WHO Round Table Discussion on Translating Research into Evidenceinformed Policy Options to Address Vitamin D Nutrition chaired by Dr Roger Bouillon and Dr Inez Schoenmakers (Oxford, UK). Short introductions were given by Dr Peˆna-Rosas, Dr ChrisTel.: Lamberg Allardt Helsinki, Finland and Dr John Pettifor Session VIII had as subject Vitamin D Nutrition and Supplementation. Dr Mairead Kiely (University College Cork, Ireland) gave a presentation on modelling of vitamin D intake and effects of food fortification. Currently dietary intake does not meet the recommended vitamin D intake and food fortification could be an effective method to increase vitamin D intake over the whole population with minimal risk for excessive dosing. Well-designed and sustainable fortification can be achieved by modeling usual food consumption intakes in representative populations. The effects of modelling of vitamin D intake and food fortification on vitamin D status were shown. Session IX had as subject Vitamin D and Immunology. Dr Chantal Mathieu (Catholic University, Leuven, Belgium) gave an overview of the relationship between vitamin D and type 1 diabetes. The antigen presenting dendritic cell plays a central role in the effect of 1,25(OH)2D on the immune system. This metabolite also induces the generation of regulator T-cells, and alters the cytokine profile of monocytes/macrophages. Transcriptome analysis showed an inhibitory effect of 1,25(OH)2D on islets of Langerhans, maybe contributing to decrease inflammation in early type 1 diabetes. The relationship between vitamin D and infectious diseases was discussed by Dr Adrian Martineau (London School of Medicine and Dentistry, Queen Mary University, London, UK). The active vitamin D metabolite stimulates the induction of protective immune responses to viral and bacterial infections. Epidemiologic studies show an association between vitamin D deficiency and susceptibility to infection and also adverse outcome. Numerous clinical trials investigate the effect of vitamin D on the number and clinical outcome of respiratory infections. Some of these show small effects on antibacterial proteins and the number of respiratory infections. Unfortunately, the Friday morning plenary lecture was cancelled due to an unanticipated issue of the keynote speaker.
Editorial / Journal of Steroid Biochemistry & Molecular Biology 164 (2016) 1–3
Therefore, the morning workshop started with Session XI on Vitamin D and its Receptor: Molecular Mechanisms. The invited presentation was by Dr Mark Meyer (University of Wisconsin, Madison, USA) on dynamic VDR control of gene expression during differentiation and selective regulation of MMP13 transcription. Cell differentiation alters transcriptomic response to 1,25(OH)2D, with many genes no longer responsive, while others show an altered, often enhanced response. Matrix metalloprotease 13 (MMP13) shows a striking increased sensitivity to 125(OH)2D upon differentiation. The enhancing activity can be blocked by deletion of 3 areas upstream of the gene. The subject of session XII was Vitamin D, muscle and cardiovascular system. The first presentation was by Dr Ralph Brandes (Goethe University, Frankfurt, Germany) on vascular regeneration. A low dose of 1,25(OH)2D enhanced carotid artery re-endothelialization and increased the number of angiogenic myeloid cells. Arteries treated with 1,25(OH)2D had a chemotactic effect on angiogenic myeloid cells, which could be blocked by SDF1 antibodies. In healthy volunteers treatment with vitamin D3 4000 IU/d increased the number of angiogenic myeloid cells. In the second presentation Dr Heike Bischoff-Ferrari (University Hospital Zurich, Switzerland) discussed the effects of high-dose vitamin D supplementation on fall incidence in the elderly. International organizations and guidelines support vitamin D supplementation as an effective intervention to prevent falling in older people. A recent randomized clinical trial in Switzerland compared a high dose of vitamin D with a lower dose and with a combination of the lower dose and calcifediol (25(OH)D). Unexpectedly, the higher dose supplementation induced higher serum 25(OH)D levels but resulted in more falls than the lower dose control intervention. Session XIII had as subject Vitamin D and Bone. The invited speaker was Dr Paul Anderson (University of South Australia, Adelaide, Australia) who spoke on the local synthesis of 1a,25(OH)2D3 in vivo. While CYP27B1 regulates bone formation in osteoblasts in vitro, the importance of the local synthesis of 1,25(OH)2D for osteoblastic function in vivo is not clear. Osteoblast specific CYP27B1KO mice were reported to exhibit normal concentrations of 1,25(OH)2D, PTH, calcium, phosphate, but a 18% reduction of trabecular bone volume in the spine. The osteoblast specific CYP27B1 transgenic mice, however showed a
3
14% increase in vertebral trabecular bone volume and an increase of trabecular thickness. These experiments show that the local synthesis of 1,25(OH)2D promotes bone formation. The last session included selected oral presentations and late breaking news. We thank the generous sponsors of the 18th Vitamin D Workshop in Delft. The Workshop received a Conference Grant (R13AG048689) from the National Institute on Aging which funded invited speakers and Young Investigator and Trainee Travel Awards. Heartland Assays sponsored again as in previous years Trainee Travel Awards. The World Health Organization (Geneva, Switzerland) generously sponsored Sessions VI and VII, including the invited speakers. Corporate sponsors included Pfizer, Chugai Pharmaceutical Co, Biotech Pharmacal Inc, Tejin Pharma Ltd, DSM, Merck, Galephar, Diasource ImmunoAssays, Cerbios, Roche Diagnostics International, Fujirebio Europe, Elsevier, Friesland Campina. Paul Lips* Department of Internal Medicine, Endocrine Section, VU University Medical Center, P.O. Box 7057 Box 7057, 1007 MB, Amsterdam, The Netherlands JoEllen Welsh University at Albany Cancer Research Center, 1 Discovery Drive Suite 304D, Rensselaer, NY 12144, United States Marie Demay Endocrine Unit, Harvard Medical School, Boston, MA 02114, United States Roger Bouillon Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, B-3000, Leuven, Belgium *Corresponding author E-mail addresses: [email protected] (P. Lips), [email protected] (J. Welsh), [email protected] (M. Demay), [email protected] (R. Bouillon).