Rapamycin promotes osteogenesis under inflammatory conditions

Li,Xing; Chang,Bei; Wang,Banchao; Bu,Wenhuan; Zhao,Liang; Liu,Jie; Meng,Lin; Wang,Lu; Xin,Ying; Wang,Dandan; Tang,Qi; Zheng,Changyu; Sun,Hongchen

doi:10.3892/mmr.2017.7693

Rapamycin promotes osteogenesis under inflammatory conditions

Authors:
- Xing Li
- Bei Chang
- Banchao Wang
- Wenhuan Bu
- Liang Zhao
- Jie Liu
- Lin Meng
- Lu Wang
- Ying Xin
- Dandan Wang
- Qi Tang
- Changyu Zheng
- Hongchen Sun
View Affiliations

Affiliations: Department of Oral Pathology, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, P.R. China, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
Published online on: October 3, 2017 https://doi.org/10.3892/mmr.2017.7693
Pages: 8923-8929
Copyright: © Li 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

Chronic periodontitis, a common oral disease, usually results in irreversible bone resorption. Bone regeneration is a complex process between bone‑forming activity of osteoblasts and bone‑resorbing activity of osteoclasts, and still remains a challenge for physicians clinically. A previous study demonstrated that the mechanistic target of rapamycin signaling pathway is involved in osteogenic differentiation of mesenchymal stromal cells. Herein, whether rapamycin could be used to induce osteogenic differentiation of primary bone marrow‑derived mesenchymal stem cells (BMSCs) in vitro and promote new bone formation in vivo were evaluated. The results demonstrated that rapamycin alone was not enough to fully induce osteoblast differentiation in vitro and enhanced bone regeneration in vivo. Interestingly, rapamycin in rapamycin plus lipopolysaccharide (LPS)‑treated BMSCs significantly increased the gene expression levels of Sp7 transcription factor, runt related transcription factor 2, alkaline phosphatase (ALP) and collagen I (Col I), ALP activity, and calcium nodule at different time points in vitro, indicating that osteoblast differentiation occurs by rapamycin when BMSCs are exposed to LPS simultaneously. It was also demonstrated that rapamycin in rapamycin plus LPS‑treated rats promoted bone regeneration in vivo. These results suggest that rapamycin may influence osteoblast differentiation and new bone formation after LPS induces an inflammatory environment. Rapamycin may be used to treat periodontitis associated with bone loss in future clinical practice.

View Figures

View References

1	Hattner R, Epker BN and Frost HM: Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling. Nature. 206:489–490. 1965. View Article : Google Scholar : PubMed/NCBI
2	Li C, Shi C, Kim J, Chen Y, Ni S, Jiang L, Zheng C, Li D, Hou J, Taichman RS and Sun H: Erythropoietin promotes bone formation through EphrinB2/EphB4 signaling. J Dent Res. 94:455–463. 2015. View Article : Google Scholar : PubMed/NCBI
3	Takayanagi H: Osteoimmunology: Shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 7:292–304. 2007. View Article : Google Scholar : PubMed/NCBI
4	Taubman MA and Kawai T: Involvement of T-lymphocytes in periodontal disease and in direct and indirect induction of bone resorption. Crit Rev Oral Biol Med. 12:125–135. 2001. View Article : Google Scholar : PubMed/NCBI
5	Dequeker J, Maenaut K, Verwilghen J and Westhovens R: Osteoporosis in rheumatoid arthritis. Clin Exp Rheumatol. 12(13 Suppl): S21–S26. 1995.
6	Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda E, Takahashi K, Furuya T, Ishiyama S, Kim KJ, et al: Activated human T cells directly induce osteoclastogenesis from human monocytes: Possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum. 44:1003–1012. 2001. View Article : Google Scholar : PubMed/NCBI
7	Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, et al: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 460:392–395. 2009.PubMed/NCBI
8	Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, et al: Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nat Med. 8:128–135. 2002. View Article : Google Scholar : PubMed/NCBI
9	Zheng N, Ding X and Jahan R: Low concentration of rapamycin inhibits hemangioma endothelial cell proliferation, migration, and vascular tumor formation in mice. Curr Ther Res Clin Exp. 76:99–103. 2014. View Article : Google Scholar : PubMed/NCBI
10	Cho HJ, Park J, Lee HW, Lee YS and Kim JB: Regulation of adipocyte differentiation and insulin action with rapamycin. Biochem Biophys Res Commun. 321:942–948. 2004. View Article : Google Scholar : PubMed/NCBI
11	Antonarakis ES, Carducci MA and Eisenberger MA: Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Cancer Lett. 291:1–13. 2010. View Article : Google Scholar : PubMed/NCBI
12	Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL and Sabatini DM: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell. 22:159–168. 2006. View Article : Google Scholar : PubMed/NCBI
13	Yang Q and Guan KL: Expanding mTOR signaling. Cell Res. 17:666–681. 2007. View Article : Google Scholar : PubMed/NCBI
14	Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP and Teitelbaum SL: TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest. 106:1481–1488. 2000. View Article : Google Scholar : PubMed/NCBI
15	Fielhaber JA, Carroll SF, Dydensborg AB, Shourian M, Triantafillopoulos A, Harel S, Hussain SN, Bouchard M, Qureshi ST and Kristof AS: Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis. J Immunol. 188:4535–4542. 2012. View Article : Google Scholar : PubMed/NCBI
16	Tulek B, Kiyan E, Toy H, Kiyici A, Narin C and Suerdem M: Anti-inflammatory and anti-fibrotic effects of sirolimus on bleomycin-induced pulmonary fibrosis in rats. Clin Invest Med. 34:E3412011. View Article : Google Scholar : PubMed/NCBI
17	Singha UK, Jiang Y, Yu S, Luo M, Lu Y, Zhang J and Xiao G: Rapamycin inhibits osteoblast proliferation and differentiation in MC3T3-E1 cells and primary mouse bone marrow stromal cells. J Cell Biochem. 103:434–446. 2008. View Article : Google Scholar : PubMed/NCBI
18	Shui C, Riggs BL and Khosla S: The immunosuppressant rapamycin, alone or with transforming growth factor-beta, enhances osteoclast differentiation of RAW264.7 monocyte-macrophage cells in the presence of RANK-ligand. Calcif Tissue Int. 71:437–446. 2002. View Article : Google Scholar : PubMed/NCBI
19	Phornphutkul C, Lee M, Voigt C, Wu KY, Ehrlich MG, Gruppuso PA and Chen Q: The effect of rapamycin on bone growth in rabbits. J Orthop Res. 27:1157–1161. 2009. View Article : Google Scholar : PubMed/NCBI
20	Viñals F, López-Rovira T, Rosa JL and Ventura V: Inhibition of PI3K/p70 S6K and p38 MAPK cascades increases osteoblastic differentiation induced by BMP-2. FEBS Lett. 510:99–104. 2002. View Article : Google Scholar : PubMed/NCBI
21	Lee KW, Yook JY, Son MY, Kim MJ, Koo DB, Han YM and Cho YS: Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP/Smad pathway. Stem Cells Dev. 19:557–568. 2010. View Article : Google Scholar : PubMed/NCBI
22	Lian JB, Javed A, Zaidi SK, Lengner C, Montecino M, van Wijnen AJ, Stein JL and Stein GS: Regulatory controls for osteoblast growth and differentiation: Role of Runx/Cbfa/AML factors. Crit Rev Eukaryot Gene Expr. 14:1–41. 2004. View Article : Google Scholar : PubMed/NCBI
23	Owen TA, Aronow M, Shalhoub V, Barone LM, Wilming L, Tassinari MS, Kennedy MB, Pockwinse S, Lian JB and Stein GS: Progressive development of the rat osteoblast phenotype in vitro: Reciprocal relationships in expression of genes associated with osteoblast proliferation and differentiation during formation of the bone extracellular matrix. J Cell Physiol. 143:420–430. 1990. View Article : Google Scholar : PubMed/NCBI
24	Stricker S, Fundele R, Vortkamp A and Mundlos S: Role of Runx genes in chondrocyte differentiation. Dev Biol. 245:95–108. 2002. View Article : Google Scholar : PubMed/NCBI
25	Mohamadnia AR, Shahbazkia HR, Sharifi S and Shafael I: Bone-specific alkaline phosphatase as a good indicator of bone formation in sheepdogs. Comp Clin Path. 16:265–270. 2007. View Article : Google Scholar
26	Matsubara T, Kida K, Yamaguchi A, Hata K, Ichida F, Meguro H, Aburatani H, Nishimura R and Yoneda T: BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. J Biol Chem. 283:29119–29125. 2008. View Article : Google Scholar : PubMed/NCBI
27	Nishio Y, Dong Y, Paris M, O'Keefe RJ, Schwarz EM and Drissi H: Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene. 372:62–70. 2006. View Article : Google Scholar : PubMed/NCBI
28	Elsubeihi ES and Heersche JN: Quantitative assessment of post-extraction healing and alveolar ridge remodelling of the mandible in female rats. Arch Oral Biol. 49:401–412. 2004. View Article : Google Scholar : PubMed/NCBI
29	Sanchez CP and He YZ: Bone growth during rapamycin therapy in young rats. BMC Pediatr. 9:32009. View Article : Google Scholar : PubMed/NCBI
30	Sun H, Kim JK, Mortensen R, Mutyaba LP, Hankenson KD and Krebsbach PH: Osteoblast-targeted suppression of PPARγ increases osteogenesis through activation of mTOR signaling. Stem Cells. 31:2183–2192. 2013. View Article : Google Scholar : PubMed/NCBI
31	Wang Y, Yi XD and Li CD: Suppression of mTOR signaling pathway promotes bone marrow mesenchymal stem cells differentiation into osteoblast in degenerative scoliosis: In vivo and in vitro. Mol Biol Rep. 44:129–137. 2017. View Article : Google Scholar : PubMed/NCBI
32	Van der Bruggen T, Nijenhuis S, van Raaij E, Verhoef J and van Asbeck BS: Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway. Infect Immun. 67:3824–3829. 1999.PubMed/NCBI
33	Fisher CJ Jr, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM and Benjamin E: Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The soluble TNF receptor sepsis study group. N Engl J Med. 334:1697–1702. 1996. View Article : Google Scholar : PubMed/NCBI
34	Glauser MP, Zanetti G, Baumgartner JD and Cohen J: Septic shock: Pathogenesis. Lancet. 338:732–736. 1991. View Article : Google Scholar : PubMed/NCBI
35	Sweet MJ and Hume DA: Endotoxin signal transduction in macrophages. J Leukoc Biol. 60:8–26. 1996.PubMed/NCBI
36	Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R and Avioli LV: Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci USA. 88:pp. 5134–5138. 1991; View Article : Google Scholar : PubMed/NCBI
37	Manolagas SC, Bellido T and Jilka RL: New insights into the cellular, biochemical, and molecular basis of postmenopausal and senile osteoporosis: Roles of IL-6 and gp130. Int J Immunopharmacol. 17:109–116. 1995. View Article : Google Scholar : PubMed/NCBI
38	Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL and Khosla S: Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone. 25:255–259. 1999. View Article : Google Scholar : PubMed/NCBI
39	Wei S, Kitaura H, Zhou P, Ross FP and Teitelbaum SL: IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest. 115:282–290. 2005. View Article : Google Scholar : PubMed/NCBI
40	Weitzmann MN, Roggia C, Toraldo G, Weitzmann L and Pacifici R: Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest. 110:1643–1650. 2002. View Article : Google Scholar : PubMed/NCBI
41	Krajewski AC, Biessei J, Kunze M, Maersch S, Perabo L and Noack MJ: Influence of lipopolysaccharide and interleukin-6 on RANKL and OPG expression and release in human periodontal ligament cells. APMIS. 117:746–754. 2009. View Article : Google Scholar : PubMed/NCBI
42	Powell N, Till S, Bungre J and Corrigan C: The immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin) inhibit allergen-induced proliferation and IL-5 production by PBMCs from atopic asthmatic patients. J Allergy Clin Immunol. 108:915–917. 2001. View Article : Google Scholar : PubMed/NCBI
43	Luo D, Ren H, Li T, Lian K and Lin D: Rapamycin reduces severity of senile osteoporosis by activating osteocyte autophagy. Osteoporos Int. 27:1093–1101. 2016. View Article : Google Scholar : PubMed/NCBI