Abstract
Purpose of Review
Fibrodysplasia ossificans progressiva (FOP) is a debilitating rare disease known for episodic endochondral heterotopic ossification (HO) caused by gain-of-function mutations in ACVR1/ALK2. However, disease severity varies among patients with identical mutations suggesting disease-modifying factors, including diet, may have therapeutic implications. The roles of vitamin D3 in calcium metabolism and chondrogenesis are known, but its effects on BMP signaling and chondrogenesis are less studied. This review attempts to assess the possibility of vitamin D’s effects in FOP by exploring relevant intersections of VD3 with mechanisms of FOP flares.
Recent Findings
In vitro and in vivo studies suggest vitamin D suppresses inflammation, while clinical studies suggest that vitamin D3 protects against arteriosclerosis and inversely correlates with non-genetic intramuscular HO. However, the enhancement of chondrogenesis, BMP signaling, and possibly Activin A expression by vitamin D may be more relevant in FOP.
Summary
There appears to be little potential for vitamin D to reduce HO in FOP, but testing the potential for excess vitamin D to promote HO may be warranted.
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References
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Bridges AJ, Hsu KC, Singh A, Churchill R, Miles J. Fibrodysplasia (myositis) ossificans progressiva. Semin Arthritis Rheum. 1994;24(3).
Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. 2008;22(1):191–205. https://doi.org/10.1016/j.berh.2007.11.007.
Dey D, Bagarova J, Hatsell SJ, Armstrong KA, Huang L, Ermann J, et al. Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci Transl Med. 2016, 8(366):366ra163. https://doi.org/10.1126/scitranslmed.aaf1090.
Baujat G, Choquet R, Bouee S, Jeanbat V, Courouve L, Ruel A, et al. Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases. Orphanet J Rare Dis. 2017;12(1):123. https://doi.org/10.1186/s13023-017-0674-5.
Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva. Pediatr Radiol. 2001;31(5):307–14. https://doi.org/10.1007/s002470100447.
Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. Pediatr Endocrinol Rev. 2013;10(2):437–48.
Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB. Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neurosurg Pediatr. 2008;1(1):91–4. https://doi.org/10.3171/PED-08/01/091.
Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38(5):525–7. https://doi.org/10.1038/ng1783.
Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303):303ra137. https://doi.org/10.1126/scitranslmed.aac4358.
Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, et al. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun. 2018;9(1):471. https://doi.org/10.1038/s41467-018-02872-2.
Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 2019;85(6):1180–7. https://doi.org/10.1111/bcp.13823.
Haviv R, Moshe V, De Benedetti F, Prencipe G, Rabinowicz N, Uziel Y. Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome? Pediatr Rheumatol Online J. 2019;17(1):84. https://doi.org/10.1186/s12969-019-0386-6.
Kaplan FS, Andolina JR, Adamson PC, Teachey DT, Finklestein JZ, Ebb DH, et al. Early clinical observations on the use of imatinib mesylate in FOP: a report of seven cases. Bone. 2018;109:276–80. https://doi.org/10.1016/j.bone.2017.07.019.
Hino K, Zhao C, Horigome K, Nishio M, Okanishi Y, Nagata S, et al. An mTOR signaling modulator suppressed heterotopic ossification of fibrodysplasia ossificans progressiva. Stem Cell Reports. 2018;11(5):1106–19. https://doi.org/10.1016/j.stemcr.2018.10.007.
Williams E, Bullock AN. Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. Bone. 2017;109:251–8. https://doi.org/10.1016/j.bone.2017.09.004.
Agarwal S, Loder SJ, Breuler C, Li J, Cholok D, Brownley C, et al. Strategic targeting of multiple BMP receptors prevents trauma-induced heterotopic ossification. Mol Ther. 2017;25(8):1974–87. https://doi.org/10.1016/j.ymthe.2017.01.008.
Sinha S, Uchibe K, Usami Y, Pacifici M, Iwamoto M. Effectiveness and mode of action of a combination therapy for heterotopic ossification with a retinoid agonist and an anti-inflammatory agent. Bone. 2016;90:59–68. https://doi.org/10.1016/j.bone.2016.02.008.
Micha D, Voermans E, Eekhoff MEW, van Essen HW, Zandieh-Doulabi B, Netelenbos C, et al. Inhibition of TGFbeta signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease. Bone. 2016;84:169–80. https://doi.org/10.1016/j.bone.2016.01.004.
Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, et al. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1R206H fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res. 2016;31:1666–75. https://doi.org/10.1002/jbmr.2820.
Pignolo RJ, Baujat G, Brown MA, De Cunto C, Di Rocco M, Hsiao EC, et al. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet Journal of Rare Diseases. 2019;14(1). https://doi.org/10.1186/s13023-019-1068-7.
Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, et al. The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment. J Bone Miner Res. 2016;31(3):650–6. https://doi.org/10.1002/jbmr.2728.
Al Kaissi A, Kenis V, Ben Ghachem M, Hofstaetter J, Grill F, Ganger R, et al. The diversity of the clinical phenotypes in patients with fibrodysplasia ossificans progressiva. J Clin Med Res. 2016;8(3):246–53. https://doi.org/10.14740/jocmr2465w.
Nguyen-Yamamoto L, Tanaka K-I, St–Arnaud R, Goltzman D. Vitamin D–regulated osteocytic sclerostin and BMP2 modulate uremic extraskeletal calcification. JCI Insight. 2019;4(13). https://doi.org/10.1172/jci.insight.126467.
. Wakahashi K, Minagawa K, Kawano Y, Kawano H, Suzuki T, Ishii S, et al. Vitamin D receptor–mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis. Blood. 2019;133(15):1619–29. https://doi.org/10.1182/blood-2018-09-876615Wakahashi et al. showed that vitamin D promotes the proinflammatory polarization of macrophages via the VDR. This could be a key mechanistic link to heterotopic ossification and FOP, as the importance of macrophages has been demonstrated in multiple mouse models of HO and FOP.
Pacifici M, Shore EM. Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders. Cytokine Growth Factor Rev. 2016;27:93–104. https://doi.org/10.1016/j.cytogfr.2015.12.007.
Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009;30(3):379–90. https://doi.org/10.1002/humu.20868.
• Hatsell SJ, Idone V, Alessi Wolken DM, Huang L, Kim HJ, Wang L, et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303) This study demonstrates that ALK2R206H is sensitized to inappropriate activation by Activin A, which is required for HO progression in the ACVR1R206H mouse model of FOP.
Alessi Wolken DM, Idone V, Hatsell SJ, Yu PB, Economides AN. The obligatory role of Activin A in the formation of heterotopic bone in fibrodysplasia ossificans progressiva. Bone. 2018;109:210–7. https://doi.org/10.1016/j.bone.2017.06.011.
Upadhyay J, Xie L, Huang L, Das N, Stewart RC, Lyon MC, et al. The expansion of heterotopic bone in fibrodysplasia ossificans progressiva is activin A-dependent. J Bone Miner Res. 2017;32(12):2489–99. https://doi.org/10.1002/jbmr.3235.
Pignolo RJ, Bedford-Gay C, Liljesthröm M, Durbin-Johnson BP, Shore EM, Rocke DM, et al. The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment. J Bone Miner Res. 2016;31(3):650–6. https://doi.org/10.1002/jbmr.2728.
Pignolo RJ, Kaplan FS. Clinical staging of fibrodysplasia ossificans progressiva (FOP). Bone. 2017;109:111–4. https://doi.org/10.1016/j.bone.2017.09.014.
Shah PB, Zasloff MA, Drummond D, Kaplan FS. Spinal deformity in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 1994;76(10):1442–50.
Gannon FH, Glaser D, Caron R, Thompson LD, Shore EM, Kaplan FS. Mast cell involvement in fibrodysplasia ossificans progressiva. Hum Pathol. 2001;32(8):842–8. https://doi.org/10.1053/hupa.2001.26464.
Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet Journal of Rare Diseases. 2011;6(1):80. https://doi.org/10.1186/1750-1172-6-80.
Cohen RB, Hahn GV, Tabas JA, Peeper J, Levitz CL, Sando A, et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am. 1993;75(2):215–9.
Kaplan FS, Tabas JA, Gannon FH, Finkel G, Hahn GV, Zasloff MA. The histopathology of fibrodysplasia ossificans progressiva. An endochondral process. J Bone Joint Surg Am. 1993;75(2):220–30. https://doi.org/10.2106/00004623-199302000-00009.
• Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, et al. Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1(R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res. 2018;33(2):269–82. https://doi.org/10.1002/jbmr.3304This represents the first demonstration that innate immune cells contribute to HO in a model of FOP that expresses the clinically relevant ALK2R206H mutation.
Merchant R, Sainani NI, Lawande MA, Pungavkar SA, Patkar DP, Walawalkar A. Pre- and post-therapy MR imaging in fibrodysplasia ossificans progressiva. Pediatr Radiol. 2006;36(10):1108–11. https://doi.org/10.1007/s00247-006-0270-7.
Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, et al. An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res. 2012;27(8):1746–56. https://doi.org/10.1002/jbmr.1637.
Smith R, Athanasou NA, Vipond SE. Fibrodysplasia (myositis) ossificans progressiva: clinicopathological features and natural history. QJM. 1996;89(6):445–6. https://doi.org/10.1093/qjmed/89.6.445.
Botman E, Raijmakers P, Yaqub M, Teunissen B, Netelenbos C, Lubbers W, et al. Evolution of heterotopic bone in fibrodysplasia ossificans progressiva: an [(18)F]NaF PET/CT study. Bone. 2019;124:1–6. https://doi.org/10.1016/j.bone.2019.03.009.
Eekhoff EMW, Botman E, Coen Netelenbos J, de Graaf P, Bravenboer N, Micha D, et al. [18F]NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva. Bone. 2018;109:143–6. https://doi.org/10.1016/j.bone.2017.08.012.
Eekhoff EMW, Netelenbos JC, de Graaf P, Hoebink M, Bravenboer N, Micha D, et al. Flare-up after maxillofacial surgery in a patient with fibrodysplasia ossificans progressiva: an [(18)F]-NaF PET/CT study and a systematic review. JBMR Plus. 2018;2(1):55–8. https://doi.org/10.1002/jbm4.10008.
Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, et al. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med. 2008;14(12):1363–9. https://doi.org/10.1038/nm.1888.
Culbert AL, Chakkalakal SA, Theosmy EG, Brennan TA, Kaplan FS, Shore EM. Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells. 2014;32(5):1289–300. https://doi.org/10.1002/stem.1633.
Dey D, Bagarova J, Hatsell SJ, Armstrong KA, Huang L, Ermann J, et al. Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification. Sci Transl Med. 2016;8(366):366ra163–366ra1. https://doi.org/10.1126/scitranslmed.aaf1090.
Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450–62. https://doi.org/10.1016/j.immuni.2016.02.015.
Kan L, Liu Y, McGuire TL, Berger DM, Awatramani RB, Dymecki SM, et al. Dysregulation of local stem/progenitor cells as a common cellular mechanism for heterotopic ossification. Stem Cells. 2009;27(1):150–6. https://doi.org/10.1634/stemcells.2008-0576.
Kan L, Lounev VY, Pignolo RJ, Duan L, Liu Y, Stock SR, et al. Substance P signaling mediates BMP-dependent heterotopic ossification. J Cell Biochem. 2011;112(10):2759–72. https://doi.org/10.1002/jcb.23259.
Hino K, Horigome K, Nishio M, Komura S, Nagata S, Zhao C, et al. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. J Clin Invest. 2017;127(9):3339–52. https://doi.org/10.1172/JCI93521.
Haviv R, Moshe V, De Benedetti F, Prencipe G, Rabinowicz N, Uziel Y. Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome? Pediatr Rheumatol. 2019;17(1). https://doi.org/10.1186/s12969-019-0386-6.
Bagarova J, Vonner AJ, Armstrong KA, Borgermann J, Lai CSC, Deng DY, et al. Constitutively active ALK2 receptor mutants require type ii receptor cooperation. Mol Cell Biol. 2013;33(12):2413–24. https://doi.org/10.1128/mcb.01595-12.
Holick MF, Frommer JE, McNeill SC, Richtand NM, Henley JW, Potts JT. Photometabolism of 7-dehydrocholesterol to previtamin D3 in skin. Biochem Biophys Res Commun. 1977;76(1):107–14. https://doi.org/10.1016/0006-291x(77)91674-6.
Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96(1):365–408. https://doi.org/10.1152/physrev.00014.2015.
Bikle DD, Schwartz J. Vitamin D binding protein, total and free vitamin D levels in different physiological and pathophysiological conditions. Front Endocrinol. 2019;10. https://doi.org/10.3389/fendo.2019.00317.
Doroudi M, Boyan BD, Schwartz Z. Rapid 1α,25(OH) 2 D 3 membrane-mediated activation of Ca 2+ /calmodulin-dependent protein kinase II in growth plate chondrocytes requires Pdia3. PLAA and caveolae. 2014;55(sup1):125–8. https://doi.org/10.3109/03008207.2014.923882.
Chen J, Doroudi M, Cheung J, Grozier AL, Schwartz Z, Boyan BD. Plasma membrane Pdia3 and VDR interact to elicit rapid responses to 1α,25(OH)2D3. Cell Signal. 2013;25(12):2362–73. https://doi.org/10.1016/j.cellsig.2013.07.020.
Pike JW, Christakos S. Biology and mechanisms of action of the vitamin D hormone. Endocrinol Metab Clin N Am. 2017;46(4):815–43. https://doi.org/10.1016/j.ecl.2017.07.001.
Jiang X, Huang B, Yang H, Li G, Zhang C, Yang G, et al. TGF-β1 is involved in vitamin D-induced chondrogenic differentiation of bone marrow-derived mesenchymal stem cells by regulating the ERK/JNK pathway. Cell Physiol Biochem. 2017;42(6):2230–41. https://doi.org/10.1159/000479997.
Asmussen N, Lin Z, McClure MJ, Schwartz Z, Boyan BD. Regulation of extracellular matrix vesicles via rapid responses to steroid hormones during endochondral bone formation. Steroids. 2019;142:43–7. https://doi.org/10.1016/j.steroids.2017.12.003.
Oishi T, Uezumi A, Kanaji A, Yamamoto N, Yamaguchi A, Yamada H, et al. Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS One. 2013;8(2):e56641. https://doi.org/10.1371/journal.pone.0056641.
Uezumi A, Fukada S, Yamamoto N, Ikemoto-Uezumi M, Nakatani M, Morita M, et al. Identification and characterization of PDGFRalpha+ mesenchymal progenitors in human skeletal muscle. Cell Death Dis. 2014;5:e1186. https://doi.org/10.1038/cddis.2014.161.
Fu B, Wang H, Wang J, Barouhas I, Liu W, Shuboy A, et al. Epigenetic regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA methylation and histone modification. PLoS One. 2013;8(4):e61423. https://doi.org/10.1371/journal.pone.0061423
Woeckel VJ, Van Der Eerden BCJ, Schreuders-Koedam M, Eijken M, Van Leeuwen JPTM. 1α,25-dihydroxyvitamin D3stimulates activin A production to fine-tune osteoblast-induced mineralization. J Cell Physiol. 2013;228(11):2167–74. https://doi.org/10.1002/jcp.24388.
Wang T-T, Tavera-Mendoza LE, Laperriere D, Libby E, Burton Macleod N, Nagai Y, et al. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005;19(11):2685–95. https://doi.org/10.1210/me.2005-0106.
Chen J, Dosier CR, Park JH, De S, Guldberg RE, Boyan BD, et al. Mineralization of three-dimensional osteoblast cultures is enhanced by the interaction of 1α,25-dihydroxyvitamin D3 and BMP2 via two specific vitamin D receptors. J Tissue Eng Regen Med. 2016;10(1):40–51. https://doi.org/10.1002/term.1770.
Garcia LA, King KK, Ferrini MG, Norris KC, Artaza JN. 1,25(OH)2Vitamin D3 stimulates myogenic differentiation by inhibiting cell proliferation and modulating the expression of promyogenic growth factors and myostatin in C2C12 skeletal muscle cells. Endocrinology. 2011;152(8):2976–86. https://doi.org/10.1210/en.2011-0159.
Braga M, Simmons Z, Norris KC, Ferrini MG, Artaza JN. Vitamin D induces myogenic differentiation in skeletal muscle derived stem cells. Endocrine Connections. 2017;6(3):139–50. https://doi.org/10.1530/ec-17-0008.
Srikuea R, Zhang X, Park-Sarge OK, Esser KA. VDR and CYP27B1 are expressed in C2C12 cells and regenerating skeletal muscle: potential role in suppression of myoblast proliferation. Am J Phys Cell Phys. 2012;303(4):C396–405. https://doi.org/10.1152/ajpcell.00014.2012.
Avcioglu G, Özbek Ipteç B, Akcan G, Görgün B, Fidan K, Carhan A, et al. Effects of 1,25-Dihydroxy vitamin D3 on TNF-α induced inflammation in human chondrocytes and SW1353 cells: a possible role for toll-like receptors. Mol Cell Biochem. 2019;464:131–42. https://doi.org/10.1007/s11010-019-03655-z.
Li W, Liu Z, Tang R, Ouyang S, Li S, Wu J. Vitamin D inhibits palmitate-induced macrophage pro-inflammatory cytokine production by targeting the MAPK pathway. Immunol Lett. 2018;202:23–30. https://doi.org/10.1016/j.imlet.2018.07.009.
Tulk SE, Liao K-C, Muruve DA, Li Y, Beck PL, Macdonald JA. Vitamin D3metabolites enhance the NLRP3-dependent secretion of IL-1β from human THP-1 monocytic cells. J Cell Biochem. 2015;116(5):711–20. https://doi.org/10.1002/jcb.24985.
Kew RR, Tabrizian T, Vosswinkel JA, Davis JE, Jawa RS. Vitamin D–binding protein deficiency in mice decreases systemic and select tissue levels of inflammatory cytokines in a murine model of acute muscle injury. J Trauma Acute Care Surg. 2018;84(6):847–54. https://doi.org/10.1097/ta.0000000000001875.
Luderer HF, Nazarian RM, Zhu ED, Demay MB. Ligand-dependent actions of the vitamin D receptor are required for activation of TGF-β signaling during the inflammatory response to cutaneous injury. 2013;154(1):16-24. doi: https://doi.org/10.1210/en.2012-1579.
Proudfoot D. Calcium signaling and tissue calcification. Cold Spring Harb Perspect Biol. 2019;11(10):a035303. https://doi.org/10.1101/cshperspect.a035303.
Pal SN, Golledge J. Osteo-progenitors in vascular calcification. J Atheroscler Thromb. 2010;18(7):551–9. https://doi.org/10.5551/jat.8656.
Rattazzi M, Faggin E, Buso R, Di Virgilio R, Puato M, Plebani M, et al. Atorvastatin reduces circulating osteoprogenitor cells and T-cell RANKL expression in osteoporotic women: implications for the bone-vascular axis. Cardiovasc Ther. 2016;34(1):13–20. https://doi.org/10.1111/1755-5922.12163.
Ma L, Ishigami M, Honda T, Yokoyama S, Yamamoto K, Ishizu Y, et al. Antifibrotic effects of 1,25(OH)2D3 on nonalcoholic steatohepatitis in female mice. Dig Dis Sci. 2019;64(9):2581–90. https://doi.org/10.1007/s10620-019-05560-3.
Hou YC, Lu CL, Zheng CM, Liu WC, Yen TH, Chen RM, et al. The role of vitamin D in modulating mesenchymal stem cells and endothelial progenitor cells for vascular calcification. Int J Mol Sci. 2020;21(7). https://doi.org/10.3390/ijms21072466.
McCabe KM, Zelt JG, Kaufmann M, Laverty K, Ward E, Barron H, et al. Calcitriol accelerates vascular calcification irrespective of vitamin K status in a rat model of chronic kidney disease with hyperphosphatemia and secondary hyperparathyroidism. J Pharmacol Exp Ther. 2018;366(3):433–45. https://doi.org/10.1124/jpet.117.247270.
Orfanidou T, Malizos KN, Varitimidis S, Tsezou A. 1,25-Dihydroxyvitamin D(3) and extracellular inorganic phosphate activate mitogen-activated protein kinase pathway through fibroblast growth factor 23 contributing to hypertrophy and mineralization in osteoarthritic chondrocytes. Exp Biol Med (Maywood). 2012;237(3):241–53. https://doi.org/10.1258/ebm.2011.011301.
Mizobuchi M, Ogata H, Koiwa F, Kinugasa E, Akizawa T. Vitamin D and vascular calcification in chronic kidney disease. Bone. 2009;45(Suppl 1):S26–9. https://doi.org/10.1016/j.bone.2009.01.011.
Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, et al. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation. 1997;96(6):1755–60. https://doi.org/10.1161/01.cir.96.6.1755.
Pirro M, Manfredelli MR, Schillaci G, Helou RS, Bagaglia F, Melis F, et al. Association between circulating osteoblast progenitor cells and aortic calcifications in women with postmenopausal osteoporosis. Nutr Metab Cardiovasc Dis. 2013;23(5):466–72. https://doi.org/10.1016/j.numecd.2011.08.006.
Han MS, Che X, Cho GH, Park HR, Lim KE, Park NR, et al. Functional cooperation between vitamin D receptor and Runx2 in vitamin D-induced vascular calcification. PLoS One. 2013;8(12):e83584. https://doi.org/10.1371/journal.pone.0083584.
Martineau C, Naja RP, Husseini A, Hamade B, Kaufmann M, Akhouayri O, et al. Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2. J Clin Investig. 2018;128(8):3546–57. https://doi.org/10.1172/jci98093.
Lee S-H, Agashe MV, Suh S-W, Yoon Y-C, Song S-H, Yang J-H, et al. Paravertebral ligament ossification in vitamin D–resistant rickets. Spine. 2012;37(13):E792–E6. https://doi.org/10.1097/brs.0b013e31824a3dc8.
Oleson CV, Seidel BJ, Zhan T. Association of vitamin D deficiency, secondary hyperparathyroidism, and heterotopic ossification in spinal cord injury. J Rehabil Res Dev. 2013;50(9):1177–86. https://doi.org/10.1682/jrrd.2012.11.0206.
Ekiz T, Demir S, Doĝan A, Özgigin N. Coexistence of heterotopic ossification of the elbow and vitamin D deficiency following stroke: can calcium and vitamin D treatment aggravate ossification? West Indian Med J. 2014. https://doi.org/10.7727/wimj.2014.076.
Hongwei M, Tiebing Q, Zhiguo L, Kemin L. Proteomics study on biomarkers for heterotopic ossification secondary to traumatic brain injuries. J Rehabil Med. 2020;52(1):1–7. https://doi.org/10.2340/16501977-2622.
Fukuda T, Kohda M, Kanomata K, Nojima J, Nakamura A, Kamizono J, et al. Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. J Biol Chem. 2009;284(11):7149–56. https://doi.org/10.1074/jbc.M801681200.
Xiao HQ, Shi W, Liu SX, Zhang B, Xu LX, Liang XL, et al. Podocyte injury is suppressed by 1,25-dihydroxyvitamin D via modulation of transforming growth factor-beta 1/bone morphogenetic protein-7 signalling in puromycin aminonucleoside nephropathy rats. Clin Exp Pharmacol Physiol. 2009;36(7):682–9. https://doi.org/10.1111/j.1440-1681.2008.05133.x.
Li A, Cong Q, Xia X, Leong WF, Yeh J, Miao D, et al. Pharmacologic calcitriol inhibits osteoclast lineage commitment via the BMP-Smad1 and IκB-NF-κB pathways. J Bone Miner Res. 2017;32(7):1406–20. https://doi.org/10.1002/jbmr.3146.
Al Saedi A, Myers D, Stupka N, Duque G. 1,25(OH)(2)D(3) ameliorates palmitate-induced lipotoxicity in human primary osteoblasts leading to improved viability and function. Bone. 2020;115672:115672. https://doi.org/10.1016/j.bone.2020.115672.
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This publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR073874 to DSP.
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Pierce, J.L., Perrien, D.S. Do Interactions of Vitamin D3 and BMP Signaling Hold Implications in the Pathogenesis of Fibrodysplasia Ossificans Progressiva?. Curr Osteoporos Rep 19, 358–367 (2021). https://doi.org/10.1007/s11914-021-00673-z
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DOI: https://doi.org/10.1007/s11914-021-00673-z