Bìol. Tvarin, 2016, vol. 18, no. 1, pp. 61–68


V. I. Krupak1#, Kh. V. Malysheva1,2#, O. К. Pavlenko3, G. I. Shafranska1, K. de Rooij4, C. W. G. M. Löwik4, R. S. Stoika1, O. G. Korchynskyi1,4

This email address is being protected from spambots. You need JavaScript enabled to view it.

1Institute of Cell Biology NAS,
14/16 Drahomanov str., Lviv 79005, Ukraine

2Insitute of Animal Biology NAAS,
38 V. Stus str., Lviv 79034, Ukraine

3Ivan Franko National University of Lviv,
4 Grushevskyi Str., Lviv 79005, Ukraine

4Leiden University Medical Center,
2 Albinusdreef, ZA Leiden 2333, The Netherlands

Rheumatoid arthritis (RA) is a severe autoimmune inflammatory disease leading to chronic pain in the joints frequently ending in patient disability and even death. Molecular mechanisms that trigger a disease and exacerbate its progression are still poorly understood. Several signaling pathways are strongly misregulated in different cell types in joints of RA patients.

It is well known that bone morphogenetic protein (BMP) and Wnt pathway are key signaling pathways that induce and support cartilage and bone formation and maintenance. We hypothesized that pituitary tumors transforming gene 1 (PTTG1) and its partner protein — PTTG1 binding protein 1 (PTTG-BP1, also called PBF1: PTTG binding factor 1) — presents a novel key system in regulating homeostasis of joint tissues and RA pathogenesis. According to our preliminary data, overexpression of PTTG1 gene leads to a drastic inhibition of Wnt signaling in target cells. Such result suggests that PTTG1/PTTG-BP1 axis serves as a new negative regulator of bone and potentially cartilage homeostasis.

In this work, we have investigated the effect of PTTG1 gene overexpression on activation of BMP and Wnt signaling pathways. We have found that ectopic expression of PTTG1 gene inhibited hBMP2/7-induced osteogenenic differentiation of C2C12 cells and bone matrix mineralization in KS483 cells. At the same time shRNA-mediated knockdown of mRNA PTTG1 gene leads to a substantial activation of bone formation in these cells. Thus, PTTG1 is an important repressor of osteogenesis, and it may be involved in skeletal tissue destruction caused by the inflammatory processes.


1. Diarra D., Stolina M., Polzer K., Zwerina J., Ominsky M. S., Dwyer D., Korb A., Smolen J., Hoffmann M., Scheinecker C., van der Heide D., Landewe R., Lacey D., Richards W. G., Schett G. Dickkopf-1 is a master regulator of joint remodeling. Nature Medicine, 2007, 13, pp. 56–63. https://doi.org/10.1038/nm1538
2. Dong J., Cui X., Jiang Z., Sun J. MicroRNA-23a modulates tumor necrosis factor-α-induced osteoblasts apoptosis by directly targeting Fas. Journal of Cellular Biochemistry, 2013, 114 (12), pp. 2738–2745. https://doi.org/10.1002/jcb.24622
3. Fujii M., Takeda K., Imamura T., Aoki H., Sampath T. K., Enomoto S., Kawabata M., Kato M., Ichijo H., Miyazono K. Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Molecular Biology of the Cell, 1999, 10 (11), pp. 3801–3813. https://doi.org/10.1091/mbc.10.11.3801
4. Galli C., Piemontese M., Lumetti S., Manfredi G. M., Passeri M. G. The importance of Wnt pathways for bone metabolism and their regulation by implant topography. European Cells and Materials, 2012, 24, pp. 46–59. https://doi.org/10.22203/eCM.v024a04
5. Issack P. S., Heflet D. L., Lane J. M. Role of Wnt signaling in bone remodeling and repair. Hospital for Special Surgery Journal, 2008, 4, pp. 66–70. https://doi.org/10.1007/s11420-007-9072-1
6. Johnson M. L., Kamel M. A. The Wnt signaling pathway and bone metabolism. Current Opinion in Rheumatology, 2007, 19, pp. 376–382. https://doi.org/10.1097/BOR.0b013e32816e06f9
7. Katagiri T., Yamaguchi A., Komaki M., Abe E., Takahashi N., Ikeda T., Rosen V., Wozney J. M., A Fujisawa-Sehara A., Suda T. Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage. The Journal of Cell Biology, 1994, 127, pp. 1755–1766. https://doi.org/10.1083/jcb.127.6.1755
8. Kitajima I., Nakajima T., Imamura T. Induction of apoptosis in murine clonal osteoblasts expressed by human T-cell leukemia virus type I tax by NF-κB and TNF-α. Journal of Bone and Mineral Research, 1996, 11 (2), pp. 200–210. https://doi.org/10.1002/jbmr.5650110209
9. Korchynskyi O., Dechering K. J., Sijbers A. M., Olijve W., ten Dijke P. Gene array analysis of bone morphogenetic protein type I receptor-induced osteoblast differentiation. Journal of Bone and Mineral Research, 2003, 18 (7), pp. 1177–1185. https://doi.org/10.1359/jbmr.2003.18.7.1177
10. Korchynskyi O. Adenoviral vectors: convenient tools for gene delivery to primary mammalian cells. Biotechnologia Acta, 2012, 5 (5), pp. 16–26.
11. Krause C., Korchynskyi O., de Rooij K., Weidauer S. E., de Gorter D. J. J., van Bezooijen R. L., Hatsell S., Economides A. N., Mueller T. D., Löwik C. W. G. M., ten Dijkee P. Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways. The Journal of Biological Chemistry, 2010, 285 (53), pp. 41614–41626. https://doi.org/10.1074/jbc.M110.153890
12. Krishnan V., Bryant H. U., MacDougald O. A. Regulation of bone mass by Wnt signaling. The Journal of Clinical Investigation, 2013, 116, pp. 1202–1209. https://doi.org/10.1172/JCI28551
13. Kwan Tat S., Padrines M., Théoleyre S. IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology, bone signaling pathways and treatment of osteoporosis. Cytokine and Growth Factor Reviews, 2003, 15, pp. 49–60.
14. Lequerré T., Bansard C., Vittecoq O., Derambure C., Hiron M., Daveau M., Tron F., Ayral X., Biga N., Auquit-Auckbur I., Chiocchia G., Le Loët X., Salier J. F. Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia. Arthritis Research & Therapy, 2009, 11 (3): R99. https://doi.org/10.1186/ar2744
15. Park J. Y., Pillinger M. H. Interleukin-6 in the pathogenesis of rheumatoid arthritis. Bulletin of the NYU Hospital for Joint Diseases, 2007, 65, pp. 4–10.
16. Pei L., Melmed S. Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Molecular Endocrinology, 1997, 4, pp. 433–441. https://doi.org/10.1210/mend.11.4.9911
17. Rawadi G., Roman-Roman S. Wnt signalling pathway: a new target for the treatment of osteoporosis. Expert Opinion on Therapeutic Targets, 2005, 9, pp. 1063–1077. https://doi.org/10.1517/14728222.9.5.1063
18. Stock M., Schäfer H., Fliegauf M., Otto F. Identification of Novel Target Genes of the Bone-Specific Transcription Factor Runx2. Journal of Bone and Mineral Research, 2004, 6, pp. 959–972. https://doi.org/10.1359/jbmr.2004.19.6.959
19. Tfelt-Hansen J., Kanuparthi D., Chattopadhyay N. The emerging role of pituitary tumor transforming gene in tumorigenesis. Clinical Medicine and Research, 2006, 4 (2), pp. 130–137. https://doi.org/10.3121/cmr.4.2.130
20. Van der Horst G., van Bezooijen R. L., Deckers M. M. Differentiation of murine preosteoblastic KS483 cells depends on autocrine bone morphogenetic protein signalling during all phases of osteoblast formation. Bone, 2003, 31 (6), pp. 661–669. https://doi.org/10.1016/S8756-3282(02)00903-1
21. Wang Z., Yu R., Melmed S. Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Molecular Endocrinology, 2001, 15, pp. 1870–1879. https://doi.org/10.1210/mend.15.11.0729
22. Zou H., McGarry T., Bernal T., Kirschner M. W. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science, 1999, 285, pp. 418–422. https://doi.org/10.1126/science.285.5426.418

Download full text in PDF format




WorldCat Logo