Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Bone and Mineral Metabolism
Published in: Journal of Bone and Mineral Metabolism 6/2009

01-11-2009 | Original Article

1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression

Authors: Sadaoki Sakai, Hironari Takaishi, Kenichiro Matsuzaki, Hironori Kaneko, Mitsuru Furukawa, Yoshiteru Miyauchi, Ayako Shiraishi, Keiji Saito, Akio Tanaka, Tadatsugu Taniguchi, Toshio Suda, Takeshi Miyamoto, Yoshiaki Toyama

Published in: Journal of Bone and Mineral Metabolism | Issue 6/2009

Login to get access

Abstract

1-Alpha, 25-dihydroxy vitamin D3 (1α,25(OH)2D3), an active form of vitamin D3, plays a critical role in calcium and bone metabolism. Although 1α,25(OH)2D3 has been used for osteoporosis therapy, the direct role of 1α,25(OH)2D3 on human osteoclastogenesis has not been well characterized. Here we show that 1α,25(OH)2D3 treatment significantly inhibited human osteoclast formation at the early stage of differentiation in a concentration-dependent manner. 1α,25(OH)2D3 inhibited the expression of nuclear factor of activated T cells c1 (NFATc1, also referred as NFAT2), an essential transcription factor for osteoclast differentiation, and upregulated the expression of interferon-β (IFN-β), a strong inhibitor of osteoclastogenesis in osteoclast progenitors. Inhibitory effects of 1α,25(OH)2D3 on osteoclastogenesis and NFATc1 expression were restored by treatment with an antibody against IFN-β, suggesting that upregulation of IFN-β by 1α,25(OH)2D3 treatment results in inhibition of NFATc1 expression, in turn interfering with osteoclast formation. Thus, our study may provide a molecular basis for the treatment of human bone diseases by 1α,25(OH)2D3 through regulation of the IFN-β and NFATc1 axis.
Literature
1.
Gallagher JC, Riggs BL, Eisman J, Hamstra A, Arnaud SB, DeLuca HF (1979) Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium. J Clin Invest 64:729–736CrossRefPubMed
2.
Okazaki T, Igarashi T, Kronenberg HM (1988) 5′-Flanking region of the parathyroid hormone gene mediates negative regulation by 1, 25-(OH)2 vitamin D3. J Biol Chem 263:2203–2208PubMed
3.
Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM (1992) Sequences in the human parathyroid hormone gene that bind the 1, 25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1, 25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 89:8097–8101CrossRefPubMed
4.
Shiraishi A, Takeda S, Masaki T, Higuchi Y, Uchiyama Y, Kubodera N, Sato K, Ikeda K, Nakamura T, Matsumoto T, Ogata E (2000) Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: distinct actions from estrogen. J Bone Miner Res 15:770–779CrossRefPubMed
5.
Uchiyama Y, Higuchi Y, Takeda S, Masaki T, Shira-Ishi A, Sato K, Kubodera N, Ikeda K, Ogata E (2002) ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis. Bone (NY) 30:582–588
6.
Sairanen S, Kärkkäinen M, Tähtelä R, Laitinen K, Mäkelä P, Lamberg-Allardt C, Välimäki MJ (2000) Bone mass and markers of bone and calcium metabolism in postmenopausal women treated with 1, 25-dihydroxyvitamin D (calcitriol) for four years. Calcif Tissue Int 67:122–127CrossRefPubMed
7.
Lukert BP, Raisz LG (1990) Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 112:352–364PubMed
8.
Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ (1984) Marked suppression of secondary hyperparathyroidism by intravenous administration of 1, 25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest 74:2136–2143CrossRefPubMed
9.
Miyamoto T, Suda T (2003) Differentiation and function of osteoclasts. Keio J Med 52:1–7PubMed
10.
Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602CrossRefPubMed
11.
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature (Lond) 397:315–323CrossRef
12.
Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, Armstrong A, Shen V, Bain S, Cosman D, Anderson D, Morrissey PJ, Peschon JJ, Schuh J (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424CrossRefPubMed
13.
Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4:353–362CrossRefPubMed
14.
Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3:889–901CrossRefPubMed
15.
Johnson RS, Spiegelman BM, Papaioannou V (1992) Pleiotropic effects of a null mutation in the c-fos proto-oncogene. Cell 71:577–586CrossRefPubMed
16.
Matsuo K, Galson DL, Zhao C, Peng L, Laplace C, Wang KZ, Bachler MA, Amano H, Aburatani H, Ishikawa H, Wagner EF (2004) Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. J Biol Chem 279:26475–26480CrossRefPubMed
17.
Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E, Takayanagi H (2005) Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 202:1261–1269CrossRefPubMed
18.
Matsuo K, Owens JM, Tonko M, Elliott C, Chambers TJ, Wagner EF (2000) Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Genet 24:184–187CrossRefPubMed
19.
Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T (2002) RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature (Lond) 416:744–749CrossRef
20.
Aloia JF, Vaswani A, Yeh JK, Ellis K, Yasumura S, Cohn SH (1988) Calcitriol in the treatment of postmenopausal osteoporosis. Am J Med 84:401–408CrossRefPubMed
21.
Takasu H, Sugita A, Uchiyama Y, Katagiri N, Okazaki M, Ogata E, Ikeda K (2006) c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs. J Clin Invest 116:528–535CrossRefPubMed
22.
Iwamoto K, Miyamoto T, Sawatani Y, Hosogane N, Hamaguchi I, Takami M, Nomiyama K, Takagi K, Suda T (2004) Ligand-independent dimer formation of receptor activator of nuclear factor kappa B (RANK) induces incomplete osteoclast formation. Biochem Biophys Res Commun 325:229–234CrossRefPubMed
23.
Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, Morita K, Ninomiya K, Suzuki T, Miyamoto K, Oike Y, Takeya M, Toyama Y, Suda T (2005) DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med 202:345–351CrossRefPubMed
24.
Morita K, Miyamoto T, Fujita N, Kubota Y, Ito K, Takubo K, Miyamoto K, Ninomiya K, Suzuki T, Iwasaki R, Yagi M, Takaishi H, Toyama Y, Suda T (2007) Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification. J Exp Med 204:1613–1623PubMed
25.
Matsumoto T, Miki T, Hagino H, Sugimoto T, Okamoto S, Hirota T, Tanigawara Y, Hayashi Y, Fukunaga M, Shiraki M, Nakamura T (2005) A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 90:5031–5036CrossRefPubMed
26.
Takahashi N, Kukita T, MacDonald BR, Bird A, Mundy GR, McManus LM, Miller M, Boyde A, Jones SJ, Roodman GD (1989) Osteoclast-like cells form in long-term human bone marrow but not in peripheral blood cultures. J Clin Invest 83:543–550CrossRefPubMed
27.
Park BK, Zhang H, Zeng Q, Dai J, Keller ET, Giordano T, Gu K, Shah V, Pei L, Zarbo RJ, McCauley L, Shi S, Chen S, Wang CY (2007) NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med 13:62–69CrossRefPubMed
28.
Miyamoto T, Ohneda O, Arai F, Iwamoto K, Okada S, Takagi K, Anderson DM, Suda T (2001) Bifurcation of osteoclasts and dendritic cells from common progenitors. Blood 98:2544–2554CrossRefPubMed
29.
Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, Hasegawa Y, Niimi H, Yanagisawa J, Tanaka T, Kato S (1998) Inactivating mutations in the 25-hydroxyvitamin D3 1α-hydroxylase gene in patients with pseudovitamin D-deficiency rickets. N Engl J Med 338:653–661CrossRefPubMed
30.
Koike N, Ichikawa F, Nishii Y, Stumpf E (1998) Sustained osteoblast nuclear receptor binding of converted 1α, 25-dihydroxyvitamin D3 after administration of 3H–1α-hydroxyvitamin D3: a combined receptor autoradiography and radioassay time course study with comparison to 3H–1α, 25-dihydroxyvitamin D3. Calcif Tissue Int 63:391–395CrossRefPubMed
Metadata
Title
1-Alpha, 25-dihydroxy vitamin D3 inhibits osteoclastogenesis through IFN-beta-dependent NFATc1 suppression
Authors
Sadaoki Sakai
Hironari Takaishi
Kenichiro Matsuzaki
Hironori Kaneko
Mitsuru Furukawa
Yoshiteru Miyauchi
Ayako Shiraishi
Keiji Saito
Akio Tanaka
Tadatsugu Taniguchi
Toshio Suda
Takeshi Miyamoto
Yoshiaki Toyama
Publication date
01-11-2009
Publisher
Springer Japan
Published in
Journal of Bone and Mineral Metabolism / Issue 6/2009
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-009-0084-4

Other articles of this Issue 6/2009

Journal of Bone and Mineral Metabolism 6/2009 Go to the issue

List of Reviewers 2008-2009

List of Reviewers 2008–2009

Original Article

The relationship between body composition and the urinary excretion of deoxypyridinoline and galactosyl-hydroxylysine in children and adolescents

Short Communication

Effect of vitamin D supplementation in the institutionalized elderly

Review Article

A review of drug-induced hypocalcemia

Original Article

The impact of lifestyle factors on serum 25-hydroxyvitamin D levels: a cross-sectional study in Japanese women aged 19–25 years

Original Article

Variation in lumbar spine bone mineral content by age and gender in apparently healthy Indians
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits