Browse > Article
http://dx.doi.org/10.1038/s12276-018-0192-0

Gender-independent efficacy of mesenchymal stem cell therapy in sex hormone-deficient bone loss via immunosuppression and resident stem cell recovery  

Sui, Bing-Dong (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Chen, Ji (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Zhang, Xin-Yi (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
He, Tao (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Zhao, Pan (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Zheng, Chen-Xi (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Li, Meng (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Hu, Cheng-Hu (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Jin, Yan (State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University)
Publication Information
Experimental and Molecular Medicine / v.50, no.12, 2018 , pp. 12.1-12.14 More about this Journal
Abstract
Osteoporosis develops with high prevalence in both postmenopausal women and hypogonadal men. Osteoporosis results in significant morbidity, but no cure has been established. Mesenchymal stem cells (MSCs) critically contribute to bone homeostasis and possess potent immunomodulatory/anti-inflammatory capability. Here, we investigated the therapeutic efficacy of using an infusion of MSCs to treat sex hormone-deficient bone loss and its underlying mechanisms. In particular, we compared the impacts of MSC cytotherapy in the two genders with the aim of examining potential gender differences. Using the gonadectomy (GNX) model, we confirmed that the osteoporotic phenotypes were substantially consistent between female and male mice. Importantly, systemic MSC transplantation (MSCT) not only rescued trabecular bone loss in GNX mice but also restored cortical bone mass and bone quality. Unexpectedly, no differences were detected between the genders. Furthermore, MSCT demonstrated an equal efficiency in rectifying the bone remodeling balance in both genders of GNX animals, as proven by the comparable recovery of bone formation and parallel normalization of bone resorption. Mechanistically, using green fluorescent protein (GFP)-based cell-tracing, we demonstrated rapid engraftment but poor inhabitation of donor MSCs in the GNX recipient bone marrow of each gender. Alternatively, MSCT uniformly reduced the $CD3^+T$-cell population and suppressed the serum levels of inflammatory cytokines in reversing female and male GNX osteoporosis, which was attributed to the ability of the MSC to induce T-cell apoptosis. Immunosuppression in the microenvironment eventually led to functional recovery of endogenous MSCs, which resulted in restored osteogenesis and normalized behavior to modulate osteoclastogenesis. Collectively, these data revealed recipient sexually monomorphic responses to MSC therapy in gonadal steroid deficiency-induced osteoporosis via immunosuppression/anti-inflammation and resident stem cell recovery.
Keywords
Citations & Related Records
연도 인용수 순위
  • Reference
1 Jackson, J. A. & Kleerekoper, M. Osteoporosis in men: diagnosis, pathophysiology, and prevention. Medicine 69, 137-152 (1990).   DOI
2 Moverare-Skrtic, S. et al. Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat. Med. 20, 1279-1288 (2014).   DOI
3 Hannan, M. T., Felson, D. T. & Anderson, J. J. Bone mineral density in elderly men and women: results from the Framingham osteoporosis study. J. Bone Miner. Res. 7, 547-553 (1992).
4 Pacifici, R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J. Bone Miner. Res. 11, 1043-1051 (1996).
5 Sui BD, et al. Stem cell-based bone regeneration in diseased microenvironments: Challenges and solutions. Biomaterials 2017; e-pub ahead of print 30 October 2017. https://doi.org/10.1016/j.biomaterials.2017.10.046.   DOI
6 Sui, B. D., Hu, C. H., Zheng, C. X. & Jin, Y. Microenvironmental Views on Mesenchymal Stem Cell Differentiation in Aging. J. Dent. Res. 95, 1333-1340 (2016).   DOI
7 Liu, Y., Wu, J., Zhu, Y. & Han, J. Therapeutic application of mesenchymal stem cells in bone and joint diseases. Clin. Exp. Med. 14, 13-24 (2014).   DOI
8 Shi, Y. et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 20, 510-518 (2010).   DOI
9 Sui, B. D. et al. Recipient Glycemic Micro-environments Govern Therapeutic Effects of Mesenchymal Stem Cell Infusion on Osteopenia. Theranostics 7, 1225-1244 (2017).   DOI
10 Liu, Y. et al. Transplantation of SHED prevents bone loss in the early phase of ovariectomy-induced osteoporosis. J. Dent. Res. 93, 1124-1132 (2014).   DOI
11 Cho, S. W. et al. Transplantation of mesenchymal stem cells overexpressing RANK-Fc or CXCR4 prevents bone loss in ovariectomized mice. Mol. Ther. 17, 1979-1987 (2009).   DOI
12 Cenci, S. et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J. Clin. Invest. 106, 1229-1237 (2000).   DOI
13 Yuan, X. et al. Psoralen and isopsoralen Ameliorate sex hormone deficiencyinduced osteoporosis in female and male mice. Biomed. Res. Int. 2016, 6869452 (2016).
14 Fujita, T. et al. Breadth of the mandibular condyle affected by disturbances of the sex hormones in ovariectomized and orchiectomized mice. Clin. Orthod. Res. 4, 172-176 (2001).   DOI
15 Cenci, S. et al. Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc. Natl Acad. Sci. USA 100, 10405-10410 (2003).   DOI
16 Wang, L. et al. IFN-gamma and TNF-alpha synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFkappaB signaling. Stem Cells 31, 1383-1395 (2013).   DOI
17 Cawthon, P. M. Gender differences in osteoporosis and fractures. Clin. Orthop. Relat. Res. 469, 1900-1905 (2011).   DOI
18 Rupich, R. C., Specker, B. L., Lieuw-A-Fa, M. & Ho, M. Gender and race differences in bone mass during infancy. Calcif. Tissue Int. 58, 395-397 (1996).   DOI
19 Gilsanz, V. et al. Gender differences in vertebral body sizes in children and adolescents. Radiology 190, 673-677 (1994).   DOI
20 Aaron, J. E., Makins, N. B. & Sagreiya, K. The microanatomy of trabecular bone loss in normal aging men and women. Clin. Orthop. Relat. Res. 215, 260-271 (1987).
21 Sui, B. et al. Allogeneic mesenchymal stem cell therapy promotes osteoblastogenesis and prevents glucocorticoid-induced osteoporosis. Stem Cells Transl. Med. 5, 1238-1246 (2016).   DOI
22 Lee, K. et al. Systemic transplantation of human adipose-derived stem cells stimulates bone repair by promoting osteoblast and osteoclast function. J. Cell. Mol. Med. 15, 2082-2094 (2011).   DOI
23 An, J. H. et al. Transplantation of human umbilical cord blood-derived mesenchymal stem cells or their conditioned medium prevents bone loss in ovariectomized nude mice. Tissue Eng. Part. A. 19, 685-696 (2013).   DOI
24 Nielson, C. M., Klein, R. F. & Orwoll, E. S. Sex and the single nucleotide polymorphism: exploring the genetic causes of skeletal sex differences. J. Bone Miner. Res. 27, 2047-2050 (2012).   DOI
25 Lien, C. Y., Chih-Yuan, Ho. K., Lee,O. K., Blunn,G. W. & Su, Y. Restoration of bone mass and strength in glucocorticoid-treated mice by systemic transplantation of CXCR4 and cbfa-1 co-expressing mesenchymal stem cells. J. Bone Miner. Res. 24, 837-848 (2009).   DOI
26 Ma, L. et al. Transplantation of mesenchymal stem cells ameliorates secondary osteoporosis through interleukin-17-impaired functions of recipient bone marrow mesenchymal stem cells in MRL/lpr mice. Stem Cell Res. Ther. 6, 104 (2015).   DOI
27 Akiyama, K. et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell. Stem Cell 10, 544-555 (2012).   DOI
28 Khosla, S., Oursler, M. J. & Monroe, D. G. Estrogen and the skeleton. Trends Endocrinol. Metab. 23, 576-581 (2012).   DOI
29 Most, W., van der Wee-Pals, L., Ederveen, A., Papapoulos, S. & Lowik, C. Ovariectomy and orchidectomy induce a transient increase in the osteoclastogenic potential of bone marrow cells in the mouse. Bone 20, 27-30 (1997).   DOI
30 Turner, R. T., Wakley, G. K. & Hannon, K. S. Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J. Orthop. Res. 8, 612-617 (1990).   DOI
31 Novack, D. V. Estrogen and bone: osteoclasts take center stage. Cell. Metab. 6, 254-256 (2007).   DOI
32 Weitzmann, M. N. & Pacifici, R. Estrogen deficiency and bone loss: an inflammatory tale. J. Clin. Invest. 116, 1186-1194 (2006).   DOI
33 Clowes, J. A., Riggs, B. L. & Khosla, S. The role of the immune system in the pathophysiology of osteoporosis. Immunol. Rev. 208, 207-227 (2005).   DOI
34 Pfeilschifter, J., Koditz, R., Pfohl, M. & Schatz, H. Changes in proinflammatory cytokine activity after menopause. Endocr. Rev. 23, 90-119 (2002).   DOI
35 Finkelstein, J. S. et al. Osteoporosis in men with idiopathic hypogonadotropic hypogonadism. Ann. Intern Med 106, 354-361 (1987).   DOI
36 Yang, N. et al. Tumor necrosis factor alpha suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J. Bone Miner. Res. 28, 559-573 (2013).   DOI
37 Liao, L. et al. TNF-alpha Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis. Stem Cells 34, 1054-1067 (2016).   DOI
38 Seeman, E. During aging, men lose less bone than women because they gain more periosteal bone, not because they resorb less endosteal bone. Calcif. Tissue Int. 69, 205-208 (2001).   DOI
39 Vandenput, L. & Ohlsson, C. Estrogens as regulators of bone health in men. Nat. Rev. Endocrinol. 5, 437-443 (2009).   DOI
40 Francis, R. M. Androgen replacement in aging men. Calcif. Tissue Int. 69, 235-238 (2001).   DOI
41 Sui, B., Hu, C. & Jin, Y. Mitochondrial metabolic failure in telomere attritionprovoked aging of bone marrow mesenchymal stem cells. Biogerontology 17, 267-279 (2016).   DOI
42 Sui, B. et al. Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis. Sci. Rep. 6, 30186 (2016).   DOI
43 Shao, B. et al. Estrogen preserves Fas ligand levels by inhibiting microRNA-181a in bone marrow-derived mesenchymal stem cells to maintain bone remodeling balance. FASEB J. 29, 3935-3944 (2015).   DOI
44 Zheng, C., Sui, B., Hu, C. & Jin, Y. Vitamin C promotes in vitro proliferation of bone marrow mesenchymal stem cells derived from aging mice. Nan. Fang. Yi. Ke. Da. Xue. Xue. Bao. 35, 1689-1693 (2015).
45 Bouxsein, M. L. et al. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J. Bone Miner. Res. 25, 1468-1486 (2010).   DOI
46 Stepan, J. J., Lachman, M., Zverina, J., Pacovsky, V. & Baylink, D. J. Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J. Clin. Endocrinol. Metab. 69, 523-527 (1989).   DOI
47 Alibhai, S. M., Gogov, S. & Allibhai, Z. Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. Crit. Rev. Oncol. Hematol. 60, 201-215 (2006).   DOI
48 Baillie, S. P., Davison, C. E., Johnson, F. J. & Francis, R. M. Pathogenesis of vertebral crush fractures in men. Age Ageing 21, 139-141 (1992).   DOI
49 Chen, N. et al. microRNA-21 Contributes to Orthodontic Tooth Movement. J. Dent. Res. 95, 1425-1433 (2016).   DOI
50 Hu, C. H. et al. miR-21 deficiency inhibits osteoclast function and prevents bone loss in mice. Sci. Rep. 7, 43191 (2017).   DOI
51 Dempster, D. W. et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 28, 2-17 (2013).   DOI
52 Zhao, P. et al. Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. Aging Cell 16, 1083-1093 (2017).   DOI
53 Liao, L. et al. Redundant miR-3077-5p and miR-705 mediate the shift of mesenchymal stem cell lineage commitment to adipocyte in osteoporosis bone marrow. Cell Death Dis. 4, e600 (2013).   DOI
54 Liu, S. et al. MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus. Cell. Metab. 22, 606-618 (2015).   DOI
55 Gunness, M. & Orwoll, E. Early induction of alterations in cancellous and cortical bone histology after orchiectomy in mature rats. J. Bone Miner. Res. 10, 1735-1744 (1995).
56 Zhang, X. S. et al. Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice. J. Gene Med. 6, 4-15 (2004).   DOI
57 Mirsaidi, A. et al. Therapeutic potential of adipose-derived stromal cells in agerelated osteoporosis. Biomaterials 35, 7326-7335 (2014).   DOI
58 Chen, C. et al. Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis. Cell Res. 27, 559-577 (2017).   DOI
59 Tan, R. et al. GAPDH is critical for superior efficacy of female bone marrowderived mesenchymal stem cells on pulmonary hypertension. Cardiovasc. Res. 100, 19-27 (2013).   DOI
60 Sammour, I. et al. The Effect of Gender on Mesenchymal Stem Cell (MSC) Efficacy in Neonatal Hyperoxia-Induced Lung Injury. PLoS ONE 11, e0164269 (2016).   DOI