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

THE PTTG1 IS A NOVEL INHIBITOR OF OSTEOGENIC DIFFERENTIATION OF MOUSE MESENCHYMAL STEM CELLS

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

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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.

Keywords: RHEUMATOID ARTHRITIS, PITUITARY TUMORS TRANSFORMING GENE 1, OSTEOGENESIS, MESENCHYMAL STEM CELLS, WNT SIGNALING PATHWAY

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