Abstract
Summary
Presently the relationship between CD28, biological marker of senescence, and ovariectomy is not well understood. We show that ovariectomy leads to CD28 loss on T cells and estrogen (E2) repletion and medicarpin (Med) inhibits this effect. We thus propose that Med/E2 prevents bone loss by delaying premature T cell senescence.
Introduction
Estrogen deficiency triggers reproductive aging by accelerating the amplification of TNF-α-producing T cells, thereby leading to bone loss. To date, no study has been carried out to explain the relationship between CD4+CD28null T cells and ovariectomy or osteoporosis. We aim to determine the effect of Ovx on CD28 expression on T cells and effects of E2 and medicarpin (a pterocarpan phytoalexin) with proven osteoprotective effect on altered T cell responses.
Methods
Adult, female Balb/c mice were taken for the study. The groups were: sham, Ovx, Ovx + Med or E2. Treatments were given daily by oral gavage. At autopsy bone marrow and spleen were flushed out and cells labelled with antibodies for FACS analysis. Serum was collected for ELISA.
Results
In Ovx mice, Med/E2 at their respective osteoprotective doses resulted in thymus involution and lowered Ovx-induced increase in serum TNF-α level and its mRNA levels in the BM T cells. Med/E2 reduced BM and spleen CD4+ T cell proliferation and prevented CD28 loss on CD4+ T cells. Further, Med abrogated TNF-α-induced loss of CD28 expression in the BM T cells.
Conclusions
To our knowledge this is the first report to determine the mechanism of CD28 loss on T cells as a result of ovariectomy. Our study demonstrates that Ovx leads to the generation of premature senescent CD4+CD28null T cells, an effect inhibited by E2 and Med. We propose that one of the mechanisms by which Med/E2 alleviates Ovx-induced bone loss is by delaying T cell senescence and enhancing CD28 expression.
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Acknowledgments
Funding from the Ministry of Health and Family Welfare and Department of Science and Technology, Government of India is acknowledged. AMT, AK, AR, and DKY are thankful to the Council of Scientific and Industrial Research for fellowship grants. We deeply acknowledge Mr Vishwakarma for hel** us in the FACS analysis. We pay our sincere thanks to Dr Naibedya Chattopadhyay for going through our manuscript and his valuable suggestions have helped us improve the manuscript.
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Supporting grants are from the Ministry of Health and Family Welfare, Council of Scientific and Industrial Research, University Grants Commission, and the Government of India. CDRI communication manuscript number 158/2010/DS.
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Tyagi, A.M., Srivastava, K., Kureel, J. et al. Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos Int 23, 1151–1161 (2012). https://doi.org/10.1007/s00198-011-1650-x
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DOI: https://doi.org/10.1007/s00198-011-1650-x