Effects of Serum from a Fibrodysplasia Ossificans Progressiva Patient on Osteoblastic Cells

Itoko Hisa, Akira Kawara, Takenobu Katagiri, Toshitsugu Sugimoto, Hiroshi Kaji

Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, Japan.
Internal Medicine 1, Shimane University Faculty of Medicine, Izumo, Japan.
Kawara Clinic, Kobe, Japan.

DOI: 10.4236/ojemd.2012.21001                

Abstract

Introduction: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. Patients and Methods: In the present study, we present a case of FOP with marked progressive ossification of extraskeletal tissues. We investigated whether soluble factors in serum would affect the osteoblast phenotype by examining the effects of serum from this patient and control subjects on mouse osteoblastic MC3T3-E1 cells. Results: The clinical findings of this patient were compatible with FOP, and direct sequence analysis of genomic DNA demonstrated the presence of a heterozygous 617G> A (R206H) mutation of activin type 1 receptor (ACVR1). Serum from the FOP patient enhanced the level of alkaline phosphatase (ALP) in Western blotting, compared with serum from the control, in MC3T3-E1 cells. Moreover, serum from the FOP patient enhanced the levels of ALP, osteocalcin and bone morphogenetic protein-2 mRNA in these cells. Conclusion: We presented a case of FOP with progressive ossification in extra-skeletal tissues with ACVR1 mutation. The present data suggest that the serum from this patient includes some soluble factors, which might enhance the osteoblast differentiation and BMP-2 expression in mouse osteoblastic cells.

Keywords

Fibrodysplasia Ossificans Progressiva; Osteoblast; Bone Morphogenetic Protein

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	J. M. Connor and D. A. Evans, “Fibrodysplasia Ossificans Progressiva: The Clinical Features and Natural History of 34 Patients,” Journal of Bone and Joint Surgery of Britain, Vol. 64, No. 1, 1982, pp. 76-83.
[2]	G. Feldman, M. Li, S. Martin, M. Urbanek, J. A. Urtizberea, M. Fardeau, M. LeMerrer, J. M. Connor, J. M. Triffitt, R. Smith, M. Muenke, F. S. Kaplan and E. M. Shore, “Fibrodysplasia Ossificans Progressiva, a Heritable Disorder of Severe Heterotopic Ossification, Maps to Human Chromosome 4q27-31,” American Journal of Human Genetics, Vol. 66, 2000, pp. 128-135. doi:10.1086/302724
[3]	F. H. Gannon, B. A. Valentine, E. M. Shore, M. A. Zasloff and F. S. Kaplan, “Acute Lymphocytic Infiltration in an Extremely Early Lesion of Fibrodysplasia Ossificans Progressiva,” Clinical and Orthopedic Related Research, Vol. 346, 1998, pp. 19-25. doi:10.1097/00003086-199801000-00005
[4]	A. B. Shafritz, E. M. Shore, F. H. Gannon, M. A. Zasloff, R. Taub, M. Muenke and F. S. Kaplan, “Overexpression of an Osteogenic Morphogen in Fibrodysplasia Ossificans Progressiva,” New England Journal of Medicine, Vol. 22, 1996, pp. 555-561. doi:10.1056/NEJM199608223350804
[5]	E. A. Olmsted, F. S. Kaplan and E. M. Shore, “Bone Morphogenic Protein-4 Regulation in Fibrodysplasia Ossificans Progressiva,” Clinical and Orthopedic Related Research, Vol. 408, 2003, pp. 331-343. doi:10.1097/00003086-200303000-00044
[6]	L. S. de la Pena, P. C. Billings, J. L. Fiori, J. Ahn, F. S. Kaplan and E. M. Shore, “Fibrodisplasia Ossificans Progressiva (FOP), a Disorder of Ectopic Osteogenesis, Mis-Regulates Cell Surface Expression and Trafficking BMPRIA,” Journal of Bone and Mineral Research, Vol. 20, No. 7, 2005, pp. 1168-1176. doi:10.1359/JBMR.050305
[7]	E. M. Shore, M. Xu, G. J. Feldman, D. A. Fenstermacher, T. J. Cho, I. H. Choi, J. M. Connor, P. Delai, D. L. Glaser, M. LeMerrer, R. Morhart, J. G. Rogers, S. Roger, J. T. Triffitt, J. A. Urtizberea, M. Zasloff, M. A. Brown and F. S. Kaplan, “A Recurrent Mutation in the BMP Type I Receptor ACVR1 Causes Inherited and Sporadic Fibrodysplasia Ossificans Progressiva,” Nature Genetics, Vol. 38, 2006, pp. 525-527. doi:10.1038/ng1783
[8]	G. Li, H. Peng, K. Corsi, A. Usas, A. Olshanski and J. Huard, “Differential Effect of BMP4 on NIH/3T3 and C2C12 Cells: Implications for Endochondral Bone Formation,” Journal of Bone and Mineral Research, Vol. 20, No. 9, 2005, pp. 1611-1623. doi:10.1359/JBMR.050513
[9]	I. Hisa, Y. Inoue, G. N. Hendy, L. Canaff, R. Kitazawa, S. Kitazawa, T. Komori, T. Sugimoto, S. Seino and H. Kaji, “Parathyroid Hormone-Responsive Smad3-Related Factor, Tmem119, Promotes Osteoblast Differentiation and Interacts with the Bone Morphogenetic Protein-Runx2 Pathway,” Journal of Biological Chemistry, Vol. 286, 2011, pp. 9787-9796. doi:10.1074/jbc.M110.179127
[10]	J. M. Wozney, V. Rosen, A. J. Celeste, L. M. Mitsock, M. J. Whitters, R. W. Kriz, R. M. Hewick and E. A. Wang, “Novel Regulators of Bone Formation: Molecular Clones and Activities,” Science, Vol. 242, No. 4885, 1988, pp. 1528-1534. doi:10.1126/science.3201241
[11]	E. Canalis, A. N. Economides and E. Gazzerro, “Bone Morphogenetic Proteins, Their Antagonists, and the Skelton,” Endocrine Reviews, Vol. 24, No. 2 2003, pp. 218-235. doi:10.1210/er.2002-0023
[12]	S. Epstein, A. M. Inzerillo, J. Caminis and M. Zaidi, “Disorders Associated with Acute Rapid and Severe Bone Loss,” Journal of Bone and Mineral Research, Vol. 18, No. 12, 2003, pp. 2083-2094. doi:10.1359/jbmr.2003.18.12.2083
[13]	E. Canalis and A. Giustina, “Glucocorticoid-Induced Osteoporosis: Summary of a Workshop,” Journal of Clinical Endocrinology & Metabolism, Vol. 86, No. 12, 2001, pp. 5681-5685. doi:10.1210/jc.86.12.5681
[14]	M. Kanatani, T. Sugimoto, H. Kaji, T. Kobayashi, K. Nishiyama, M. Fukase, M. Kumegawa and K. Chihara, “Stimulatory Effect of Bone Morphogenetic Protein-2 on Osteoclast-Like Cell Formation and Bone Resorbing Activity,” Journal of Bone and Mineral Research, Vol. 10, No. 11, 1995, pp. 1681-1690. doi:10.1002/jbmr.5650101110
[15]	H. Kaneko, T. Arakawa, H. Mano, T. Kaneda, A. Ogasawara, M. Nakagawa, Y. Toyama, Y. Yabe, M. Kumegawa and Y. Hakeda, “Direct Stimulation of Osteoclastic Bone Resorption by Bone Morphognetic Protein (BMP)-2 and Expression of BMP Receptors in Mature Osteoclasts,” Bone, Vol. 27, No. 24, 2000, pp. 479-486. doi:10.1016/S8756-3282(00)00358-6
[16]	M. Okamoto, J. Murai, H. Yoshikawa and N. Tsumaki, “Bone Morphogenetic Proteins in Bone Stimulate Osteoclasts and Osteoblasts during Bone Development,” Journal of Bone and Mineral Research, Vol. 21, No. 7, 2006, pp. 1022-1033. doi:10.1359/jbmr.060411
[17]	Y. Miyachi, H. Yotsumoto, T. Kano, A. Mizuchi, T. Muto and L. Yanagibashi, “Blood Levels of Synthetic Glucocorticoids after Administration by Various Routes,” Journal of Endocrinology, Vol. 82, 1978, pp. 149-157. doi:10.1677/joe.0.0820149