Dimethyloxaloylglycine increases bone repair capacity of adipose-derived stem cells in the treatment of osteonecrosis of the femoral head

Zhu,Zhen‑Hong; Song,Wen‑Qi; Zhang,Chang‑Qing; Yin,Ji‑Min

doi:10.3892/etm.2016.3698

Dimethyloxaloylglycine increases bone repair capacity of adipose-derived stem cells in the treatment of osteonecrosis of the femoral head

Authors:
- Zhen‑Hong Zhu
- Wen‑Qi Song
- Chang‑Qing Zhang
- Ji‑Min Yin
View Affiliations

Affiliations: Department of Orthopedic Surgery, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, P.R. China
Published online on: September 13, 2016 https://doi.org/10.3892/etm.2016.3698
Pages: 2843-2850
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mesenchymal stem cells have been widely studied to promote local bone regeneration of osteonecrosis of the femoral head (ONFH). Previous studies observed that dimethyloxaloylglycine (DMOG) enhanced the angiogenic and osteogenic activity of mesenchymal stem cells by activating the expression of hypoxia inducible factor‑1α (HIF‑1α), thereby improving the bone repair capacity of mesenchymal stem cells. In the present study, it was investigated whether DMOG could increase the bone repair capacity of adipose‑derived stem cells (ASCs) in the treatment of ONFH. Western blot analysis was performed to detect HIF‑1α protein expression in ASCs treated with different concentrations of DMOG. The results showed DMOG enhanced HIF‑1α expression in ASCs in a dose‑dependent manner at least for 7 days. Furthermore, DMOG‑treated ASCs were transplanted into the necrotic area of a rabbit model of ONFH to treat the disease. Four weeks later, micro‑computed tomography (CT) quantitative analysis showed that 58.8±7.4% of the necrotic area was regenerated in the DMOG‑treated ASCs transplantation group, 45.5±3.4% in normal ASCs transplantation group, 25.2±2.8% in only core decompression group and 10.6±2.6% in the untreated group. Histological analysis showed that transplantation of DMOG‑treated ASCs clearly improved the bone regeneration of the necrotic area compared with the other three groups. Micro‑CT and immunohistochemical analysis demonstrated the revasculation of the necrotic area were also increased significantly in the DMOG‑treated ASC group compared with the control groups. Thus, it is hypothesized that DMOG could increase the bone repair capacity of ASCs through enhancing HIF‑1α expression in the treatment of ONFH.

View Figures

View References

1	Kerachian MA, Harvey EJ, Cournoyer D, Chow TY and Séguin C: Avascular necrosis of the femoral head: Vascular hypotheses. Endothelium. 13:237–244. 2006. View Article : Google Scholar : PubMed/NCBI
2	Bachiller FG, Caballer AP and Portal LF: Avascular necrosis of the femoral head after femoral neck fracture. Clin Orthop Relat Res. 87–109. 2002. View Article : Google Scholar : PubMed/NCBI
3	Lieberman JR, Berry DJ, Mont MA, Aaron RK, Callaghan JJ, Rajadhyaksha AD and Urbaniak JR: Osteonecrosis of the hip: Management in the 21st century. Instr Course Lect. 52:337–355. 2003.PubMed/NCBI
4	Yoon TR, Song EK, Rowe SM and Park CH: Failure after core decompression in osteonecrosis of the femoral head. Int Orthop. 24:316–318. 2001. View Article : Google Scholar : PubMed/NCBI
5	Yuan J, Cui L, Zhang WJ, Liu W and Cao Y: Repair of canine mandibular bone defects with bone marrow stromal cells and porous beta-tricalcium phosphate. Biomaterials. 28:1005–1013. 2007. View Article : Google Scholar : PubMed/NCBI
6	Liu G, Zhao L, Zhang W, Cui L, Liu W and Cao Y: Repair of goat tibial defects with bone marrow stromal cells and beta-tricalcium phosphate. J Mater Sci Mater Med. 19:2367–2376. 2008. View Article : Google Scholar : PubMed/NCBI
7	Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schümichen C, Nienaber CA, Freund M and Steinhoff G: Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 361:45–46. 2003. View Article : Google Scholar : PubMed/NCBI
8	Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, et al: Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 355:1210–1221. 2006. View Article : Google Scholar : PubMed/NCBI
9	Dadon-Nachum M, Sadan O, Srugo I, Melamed E and Offen D: Differentiated mesenchymal stem cells for sciatic nerve injury. Stem Cell Rev. 7:664–671. 2011. View Article : Google Scholar : PubMed/NCBI
10	Yang Y, Hallgrimsson B and Putnins EE: Craniofacial defect regeneration using engineered bone marrow mesenchymal stromal cells. J Biomed Mater Res A. 99:74–85. 2011. View Article : Google Scholar : PubMed/NCBI
11	Gangji V, De Maertelaer V and Hauzeur JP: Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: Five year follow-up of a prospective controlled study. Bone. 49:1005–1009. 2011. View Article : Google Scholar : PubMed/NCBI
12	Tzaribachev N, Vaegler M, Schaefer J, Reize P, Rudert M, Handgretinger R and Müller I: Mesenchymal stromal cells: A novel treatment option for steroid-induced avascular osteonecrosis. Isr Med Assoc J. 10:232–234. 2008.PubMed/NCBI
13	Cowan CM, Shi YY, Aalami OO, Chou YF, Mari C, Thomas R, Quarto N, Contag CH, Wu B and Longaker MT: Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 22:560–567. 2004. View Article : Google Scholar : PubMed/NCBI
14	Dudas JR, Marra KG, Cooper GM, Penascino VM, Mooney MP, Jiang S, Rubin JP and Losee JE: The osteogenic potential of adipose-derived stem cells for the repair of rabbit calvarial defects. Ann Plast Surg. 56:543–548. 2006. View Article : Google Scholar : PubMed/NCBI
15	Nikol S, Engelmann MG, Pelisek J, Fuchs A, Golda A, Shimizu M, Mekkaoui C and Rolland PH: Local perivascular application of low amounts of a plasmid encoding for vascular endothelial growth factor (VEGF165) is efficient for therapeutic angiogenesis in pigs. Acta Physiol Scand. 176:151–159. 2002. View Article : Google Scholar : PubMed/NCBI
16	Elçin YM, Dixit V and Gitnick G: Extensive in vivo angiogenesis following controlled release of human vascular endothelial cell growth factor: Implications for tissue engineering and wound healing. Artif Organs. 25:558–565. 2001. View Article : Google Scholar : PubMed/NCBI
17	Mazumdar J, Dondeti V and Simon MC: Hypoxia-inducible factors in stem cells and cancer. J Cell Mol Med. 13:4319–4328. 2009. View Article : Google Scholar : PubMed/NCBI
18	Zou D, Zhang Z, Ye D, Tang A, Deng L, Han W, Zhao J, Wang S, Zhang W, Zhu C, et al: Repair of critical-sized rat calvarial defects using genetically engineered bone marrow-derived mesenchymal stem cells overexpressing hypoxia-inducible factor-1α. Stem Cells. 29:1380–1390. 2011.PubMed/NCBI
19	Ding H, Gao YS, Hu C, Wang Y, Wang CG, Yin JM, Sun Y and Zhang CQ: HIF-1α transgenic bone marrow cells can promote tissue repair in cases of corticosteroid-induced osteonecrosis of the femoral head in rabbits. PLoS One. 8:e636282013. View Article : Google Scholar : PubMed/NCBI
20	Cesana D, Ranzani M, Volpin M, Bartholomae C, Duros C, Artus A, Merella S, Benedicenti F, Sergi L Sergi, Sanvito F, et al: Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo. Mol Ther. 22:774–785. 2014. View Article : Google Scholar : PubMed/NCBI
21	Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, et al: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 292:468–472. 2001. View Article : Google Scholar : PubMed/NCBI
22	Ding H, Gao YS, Wang Y, Hu C, Sun Y and Zhang C: Dimethyloxaloylglycine increases the bone healing capacity of adipose-derived stem cells by promoting osteogenic differentiation and angiogenic potential. Stem Cells Dev. 23:990–1000. 2014. View Article : Google Scholar : PubMed/NCBI
23	National Research Council Institute for Laboratory Animal Research, . Guide for the Care and Use of Laboratory Animals. National Academies Press; Washington, DC: 1996
24	Ding H, Chen S, Yin JH, Xie XT, Zhu ZH, Gao YS and Zhang CQ: Continuous hypoxia regulates the osteogenic potential of mesenchymal stem cells in a time-dependent manner. Mol Med Rep. 10:2184–2190. 2014.PubMed/NCBI
25	Qin L, Zhang G, Sheng H, Yeung KW, Yeung HY, Chan CW, Cheung WH, Griffith J, Chiu KH and Leung KS: Multiple bioimaging modalities in evaluation of an experimental osteonecrosis induced by a combination of lipopolysaccharide and methylprednisolone. Bone. 39:863–871. 2006. View Article : Google Scholar : PubMed/NCBI
26	Sun Y, Feng Y and Zhang C: The effect of bone marrow mononuclear cells on vascularization and bone regeneration in steroid-induced osteonecrosis of the femoral head. Joint Bone Spine. 76:685–690. 2009. View Article : Google Scholar : PubMed/NCBI
27	Griffith JF, Antonio GE, Kumta SM, Hui DS, Wong JK, Joynt GM, Wu AK, Cheung AY, Chiu KH, Chan KM, et al: Osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids. Radiology. 235:168–175. 2005. View Article : Google Scholar : PubMed/NCBI
28	Ohzono K, Saito M, Sugano N, Takaoka K and Ono K: The fate of nontraumatic avascular necrosis of the femoral head. A radiologic classification to formulate prognosis. Clin Orthop Relat Res. 277:73–78. 1992.
29	Hopson CN and Siverhus SW: Ischemic necrosis of the femoral head. Treatment by core decompression. J Bone Joint Surg Am. 70:1048–1051. 1988.PubMed/NCBI
30	Maniwa S, Nishikori T, Furukawa S, Kajitani K, Iwata A, Nishikawa U and Ochi M: Evaluation of core decompression for early osteonecrosis of the femoral head. Arch Orthop Trauma Surg. 120:241–244. 2000. View Article : Google Scholar : PubMed/NCBI
31	Dailiana ZH, Toth AP, Gunneson E, Berend KR and Urbaniak JR: Free vascularized fibular grafting following failed core decompression for femoral head osteonecrosis. J Arthroplasty. 22:679–688. 2007. View Article : Google Scholar : PubMed/NCBI
32	Scully SP, Aaron RK and Urbaniak JR: Survival analysis of hips treated with core decompression or vascularized fibular grafting because of avascular necrosis. J Bone Joint Surg Am. 80:1270–1275. 1998.PubMed/NCBI
33	Jones JP Jr: Concepts of etiology and early pathogenesis of osteonecrosis. Instr Course Lect. 43:499–512. 1994.PubMed/NCBI
34	Hernigou P, Beaujean F and Lambotte JC: Decrease in the mesenchymal stem-cell pool in the proximal femur in corticosteroid-induced osteonecrosis. J Bone Joint Surg Br. 81:349–355. 1999. View Article : Google Scholar : PubMed/NCBI
35	Gangji V, Hauzeur JP, Schoutens A, Hinsenkamp M, Appelboom T and Egrise D: Abnormalities in the replicative capacity of osteoblastic cells in the proximal femur of patients with osteonecrosis of the femoral head. J Rheumatol. 30:348–351. 2003.PubMed/NCBI
36	Lee JS, Lee JS, Roh HL, Kim CH, Jung JS and Suh KT: Alterations in the differentiation ability of mesenchymal stem cells in patients with nontraumatic osteonecrosis of the femoral head: Comparative analysis according to the risk factor. J Orthop Res. 24:604–609. 2006. View Article : Google Scholar : PubMed/NCBI
37	Yan ZQ, Chen YS, Li WJ, Yang Y, Huo JZ, Chen ZR, Shi JH and Ge JB: Treatment of osteonecrosis of the femoral head by percutaneous decompression and autologous bone marrow mononuclear cell infusion. Chin J Traumatol. 9:3–7. 2006.PubMed/NCBI
38	Riddle RC, Khatri R, Schipani E and Clemens TL: Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling. J Mol Med (Berl). 87:583–590. 2009. View Article : Google Scholar : PubMed/NCBI
39	Piret JP, Lecocq C, Toffoli S, Ninane N, Raes M and Michiels C: Hypoxia and CoCl2 protect HepG2 cells against serum deprivation- and t-BHP-induced apoptosis: A possible anti-apoptotic role for HIF-1. Exp Cell Res. 295:340–349. 2004. View Article : Google Scholar : PubMed/NCBI
40	Ockaili R, Natarajan R, Salloum F, Fisher BJ, Jones D, Fowler AA III and Kukreja RC: HIF-1 activation attenuates postischemic myocardial injury: Role for heme oxygenase-1 in modulating microvascular chemokine generation. Am J Physiol Heart Circ Physiol. 289:H542–H548. 2005. View Article : Google Scholar : PubMed/NCBI
41	Milkiewicz M, Pugh CW and Egginton S: Inhibition of endogenous HIF inactivation induces angiogenesis in ischaemic skeletal muscles of mice. J Physiol. 560:21–26. 2004. View Article : Google Scholar : PubMed/NCBI
42	Nagel S, Papadakis M, Chen R, Hoyte LC, Brooks KJ, Gallichan D, Sibson NR, Pugh C and Buchan AM: Neuroprotection by dimethyloxalylglycine following permanent and transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 31:132–143. 2011. View Article : Google Scholar : PubMed/NCBI
43	Ding H, Chen S, Song WQ, Gao YS, Guan JJ, Wang Y, Sun Y and Zhang CQ: Dimethyloxaloylglycine improves angiogenic activity of bone marrow stromal cells in the tissue-engineered bone. Int J Biol Sci. 10:746–756. 2014. View Article : Google Scholar : PubMed/NCBI