BMP-2 transgenic alveolar bone-derived marrow stem cells attenuate osteonecrosis of the femoral head
Background: Osteonecrosis of the femoral head (ONFH) results in activity-related hip pain and disability, affecting around 20 million people worldwide. However, there is absent of effective therapeutic approaches for ONFH. The transplantation of mesenchymal stem cells was reported to be a promising method for ONFH therapy. In this study, we explored if bone morphogenetic protein-2 (BMP-2) transgenic alveolar bone-derived marrow stem cells (ABMSCs) could be applied to treat ONFH.
Methods: We established an ONFH mouse model by injection of steroid, and implanted ABMSCs and BMP-2 transgenic ABMSCs into the steroid-impaired femoral head. Gene expression and the pathological alternation of the tissues were analyzed by qRT-PCR and hematoxylin and eosin staining, respectively. Tartrate-resistant acid phosphatase staining was applied to detect osteoclastogenesis. Enzyme linked immunosorbent assay (ELISA) and Western blot were performed to evaluate the protein expression in the sera and tissues, respectively.
Results: ABMSCs attenuated steroid-induced ONFH and ameliorated the serum concentration of osteogenesis-associated proteins in the ONFH mice. Mechanistically, ABMSCs inhibited osteoclast differentiation by inactivating the RANKL/RANK/OPG signaling pathway. BMP-2 overexpression enhanced ABMSCs to alleviate ONFH.
Conclusions: ABMSCs and BMP-2 Transgenic ABMSCs attenuate ONFH by promoting osteoblastogenesis and inhibiting osteoclastogenesis via inactivating the RANKL/RANK/OPG signaling pathway.
Bachiller FG, Caballer AP, Portal LF. Avascular necrosis of the femoral head after femoral neck fracture. Clin Orthop Relat Res 2002; 399: 87–109. doi: 10.1097/00003086-200206000-00012
Kerachian MA, Harvey EJ, Cournoyer D, Chow TY, Seguin C. Avascular necrosis of the femoral head: vascular hypotheses. Endothelium 2006; 13(4):237–44. doi: 10.1080/10623320600904211
Cui L, Zhuang Q, Lin J, Jin J, Zhang K, Cao L, et al. Multicentric epidemiologic study on six thousand three hundred and ninety five cases of femoral head osteonecrosis in China. Int Orthop 2016; 40: 267–76. doi: 10.1007/s00264-015-3061-7
Gou WL, Lu Q, Wang X, Wang Y, Peng J, Lu SB. Key pathway to prevent the collapse of femoral head in osteonecrosis. Eur Rev Med Pharmacol Sci 2015; 19(15): 2766–74.
Amanatullah DF, Strauss EJ, Di Cesare PE. Current management options for osteonecrosis of the femoral head: part II, operative management. Am J Orthop 2011; 40(10): E216–225.
Fu C, Shi R. Osteoclast biology in bone resorption: a review. STEMedicine 2020; 1(4): e57. 10.37175/stemedicine.v1i4.57
Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKEy Rep 2014; 3: 481. doi: 10.1038/bonekey.2013.215
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423: 337–42. doi: 10.1038/nature01658
Baker N, Boyette LB, Tuan RS. Characterization of bone marrow-derived mesenchymal stem cells in aging. Bone 2015; 70: 37–47. doi: 10.1016/j.bone.2014.10.014
Mont MA, Jones LC, Einhorn TA, Hungerford DS, Reddi AH. Osteonecrosis of the femoral head. Potential treatment with growth and differentiation factors. Clin Orthop Relat Res 1998(355 Suppl): S314–335. doi: 10.1097/00003086-199810001-00032
Hang D, Wang Q, Guo C, Chen Z, Yan Z. Treatment of osteonecrosis of the femoral head with VEGF165 transgenic bone marrow mesenchymal stem cells in mongrel dogs. Cells Tissues Organs 2012; 195(6): 495–506. 10.1159/000329502
Tang TT, Lu B, Yue B, Xie XH, Xie YZ, Dai KR, et al. Treatment of osteonecrosis of the femoral head with hBMP-2-gene-modified tissue-engineered bone in goats. J Bone Joint Surg 2007;89(1):127–9. doi: 10.1302/0301-620X.89B1.18350
Wen Q, Ma L, Chen YP, Yang L, Luo W, Wang XN. Treatment of avascular necrosis of the femoral head by hepatocyte growth factor-transgenic bone marrow stromal stem cells. Gene Ther 2008; 15: 1523–35. doi: 10.1038/gt.2008.110
Lim KT, Jin H, Seonwoo H, Kim HB, Kim J, Kim JW, et al. Physical stimulation-based osteogenesis: effect of secretion in vitro on fluid dynamic shear stress of human alveolar bone-derived mesenchymal stem cells. IEEE Trans Nanobioscience 2016; 15(8): 881–90. doi: 10.1109/TNB.2016.2627053
Wen Q, Jin D, Zhou CY, Zhou MQ, Luo W, Ma L. HGF-transgenic MSCs can improve the effects of tissue self-repair in a rabbit model of traumatic osteonecrosis of the femoral head. PloS One 2012; 7(5): e37503. doi: 10.1371/journal.pone.0037503
Mikami T, Ichiseki T, Kaneuji A, Ueda Y, Sugimori T, Fukui K, et al. Prevention of steroid-induced osteonecrosis by intravenous administration of vitamin E in a rabbit model. J Orthop Sci 2010; 15(5): 674–7. doi: 10.1007/s00776-010-1516-7
Brazier M, Kamel S, Maamer M, Agbomson F, Elesper I, Garabedian M, et al. Markers of bone remodeling in the elderly subject: effects of vitamin D insufficiency and its correction. J Bone Miner Res 1995; 10: 1753–61. doi: 10.1002/jbmr.5650101119
Zaidi M, Sun L, Robinson LJ, Tourkova IL, Liu L, Wang Y, et al. ACTH protects against glucocorticoid-induced osteonecrosis of bone. Proc Natl Acad Sci U S A. 2010;107:8782-8787. doi: 10.1073/pnas.0912176107
Pietrogrande V, Marino V. Study of the circulation of the femoral head in some patients with arthritis deformans of the hip. Reumatismo 1953; 5(suppl 2): 219–22.
Wang A, Ren M, Wang J. The pathogenesis of steroid-induced osteonecrosis of the femoral head: a systematic review of the literature. Gene 2018; 10: 103–9. doi: 10.1016/j.gene.2018.05.091
Chemel M, Brion R, Segaliny AI, Lamora A, Charrier C, Brulin B, et al. Bone morphogenetic protein 2 and transforming growth factor beta1 inhibit the expression of the proinflammatory cytokine IL-34 in rheumatoid arthritis synovial fibroblasts. Am J Pathol 2017; 187: 156–62. doi: 10.1016/j.ajpath.2016.09.015
Nguyen V, Meyers CA, Yan N, Agarwal S, Levi B, James AW. BMP-2-induced bone formation and neural inflammation. J Orthop 2017; 14(2):252–6. doi: 10.1016/j.jor.2017.03.003
Huang RL, Sun Y, Ho CK, Liu K, Tang QQ, Xie Y, et al. IL-6 potentiates BMP-2-induced osteogenesis and adipogenesis via two different BMPR1A-mediated pathways. Cell Death Dis 2018;9(2):144. doi: 10.1038/s41419-017-0126-0
Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988; 242(4885): 1528–34. doi: 10.1126/science.3201241
Carreira AC, Lojudice FH, Halcsik E, Navarro RD, Sogayar MC, Granjeiro JM. Bone morphogenetic proteins: facts, challenges, and future perspectives. J Dent Res 2014; 93: 335–45. doi: 10.1177/0022034513518561
Wu M, Chen G, Li YP. TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009. doi: 10.1038/boneres.2016.9
Wagner EF, Karsenty G. Genetic control of skeletal development. Curr Opin Genet Dev 2001; 11(5):527–32. doi: 10.1016/S0959-437X(00)00228-8
Liu J, Yu F, Sun Y, Jiang B, Zhang W, Yang J, et al. Concise reviews: characteristics and potential applications of human dental tissue-derived mesenchymal stem cells Stem Cells 2015; 33(3): 627–38. doi: 10.1002/stem.1909
Wang F, Zhou Y, Zhou J, Xu M, Zheng W, Huang W, et al. Comparison of intraoral bone regeneration with iliac and alveolar BMSCs. J Dent Res 2018; 97: 1229–35. doi: 10.1177/0022034518772283
Copyright (c) 2023 Xiuxiu Hou, Baoheng Xing, Guochen Zhang, Hao Wu, Nana Feng, Yunmei Li, Guangpu Han
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain full copyright to their individual works, and publishing rights without restrictions.
In accordance with the Budapest Open Access Initiative, articles published in STEMedicine are freely available "on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited."
Except where otherwise noted, all content on this website is licensed under a Creative Commons Attribution 4.0 License. This license allows for commercial and non-commercial redistribution as well as modifications of the work as long as attribution is given to the authors and STEMedicine as the original publication source, and a link to the article on the STEMedicine website is provided.