Effect of glucocorticoids on osteoclast function in a mouse model of bone necrosis

He,Ming; Wang,Jiashi; Wang,Guangbin; Tian,Ye; Jiang,Linlin; Ren,Zhaozhou; Qiu,Chuang; Fu,Qin

doi:10.3892/mmr.2016.5368

Effect of glucocorticoids on osteoclast function in a mouse model of bone necrosis

Authors:
- Ming He
- Jiashi Wang
- Guangbin Wang
- Ye Tian
- Linlin Jiang
- Zhaozhou Ren
- Chuang Qiu
- Qin Fu
View Affiliations

Affiliations: Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: June 6, 2016 https://doi.org/10.3892/mmr.2016.5368
Pages: 1054-1060
Copyright: © He 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

Osteonecrosis, also termed aseptic necrosis, is the cellular death of bone components due to interruption of the blood supply. Glucocorticoid (GC) therapy is a common non-traumatic cause of osteonecrosis. However, the mechanism by which GCs induce osteonecrosis remains to be elucidated. The aim of the present study was to investigate the effects of GCs on osteoclast and osteoblast differentiation and function in a GC‑induced osteonecrosis mouse model. BALB/c male mice (n=40; 4‑weeks‑old) were treated with dexamethasone and asparaginase for 8 weeks. The control group (n=20) was administered normal saline. The results demonstrated that the GC-treated group had a lower mean weight compared with the control group. Morphologically, 16/37 (43%) mice demonstrated significant osteonecrotic lesions in the GC‑treated group. However, osteonecrotic lesions were not observed in the mice of the control group. Furthermore, immunohistochemistry demonstrated that the GC‑treated group had a higher level of osteoprotegerin compared with the control group, without any change in the expression of receptor activator of nuclear factor‑κB ligand. In addition, tartarate‑resistant acid-phosphatase staining demonstrated significantly decreased osteoclasts in the areas of bone destruction in the GCs-treated group. Furthermore, the present study demonstrated that GCs increased expression levels of osterix and osteocalcin, and decreased expression of matrix metallopeptidase‑9 to regulate the differentiation and function of osteoblasts and osteoclasts. The results of the present study suggested that GCs influence bone remolding resulting in decreased osteoclasts formation/differentiation. Therefore, regulating the differentiation and activity of the osteoclasts may be beneficial to the control and treatment of osteonecrosis.

View Figures

View References

1	DiGiovanni CW, Patel A, Calfee R and Nickisch F: Osteonecrosis in the foot. J Am Acad Orthop Surg. 15:208–217. 2007. View Article : Google Scholar : PubMed/NCBI
2	Lafforgue P: Pathophysiology and natural history of avascular necrosis of bone. Joint Bone Spine. 73:500–507. 2006. View Article : Google Scholar : PubMed/NCBI
3	Powell C, Chang C and Gershwin ME: Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clin Rev Allergy Immunol. 41:102–113. 2011. View Article : Google Scholar
4	Chao YC, Wang SJ, Chu HC, Chang WK and Hsieh TY: Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint, pancreatitis and cirrhosis of the liver. Alcohol. 38:431–436. 2003. View Article : Google Scholar
5	Juéry P: Avascular necrosis after a steroid injection. CMAJ. 176:814author reply 814. 2007. View Article : Google Scholar : PubMed/NCBI
6	Baksi DP: Treatment of post-traumatic avascular necrosis of the femoral head by multiple drilling and muscle-pedicle bone grafting. Preliminary report. J Bone Joint Surg Br. 65:268–273. 1983.PubMed/NCBI
7	Lee CK and Hansen HR: Post-traumatic avascular necrosis of the humeral head in displaced proximal humeral fractures. J Trauma. 21:788–791. 1981. View Article : Google Scholar : PubMed/NCBI
8	Laroche M: Intraosseous circulation from physiology to disease. Joint Bone Spine. 69:262–269. 2002. View Article : Google Scholar : PubMed/NCBI
9	Dannemann C, Grätz KW, Riener MO and Zwahlen RA: Jaw osteonecrosis related to bisphosphonate therapy: A severe secondary disorder. Bone. 40:828–834. 2007. View Article : Google Scholar : PubMed/NCBI
10	Martí-Carvajal A, Dunlop R and Agreda-Perez L: Treatment for avascular necrosis of bone in people with sickle cell disease. Cochrane Database Syst Rev. 4:CD0043442004.PubMed/NCBI
11	Levasseur R: Mechanisms of osteonecrosis. Joint Bone Spine. 75:639–642. 2008. View Article : Google Scholar : PubMed/NCBI
12	Yamamoto T, Hirano K, Tsutsui H, Sugioka Y and Sueishi K: Corticosteroid enhances the experimental induction of osteonecrosis in rabbits with Shwartzman reaction. Clin Orthop Relat Res. (316): 235–243. 1995.PubMed/NCBI
13	Yamamoto T, Irisa T, Sugioka Y and Sueishi K, Yamamoto T, Irisa T, Sugioka Y and Sueishi K: Effects of pulse methylprednisolone on bone and marrow tissues: Corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum. 40:2055–2064. 1997. View Article : Google Scholar : PubMed/NCBI
14	Kabata T, Kubo T, Matsumoto T, Hirata T, Fujioka M, Takahashi KA, Yagishita S, Kobayashi M and Tomita K: Onset of steroid-induced osteonecrosis in rabbits and its relationship to hyperlipaemia and increased free fatty acids. Rheumatology. 44:1233–1237. 2005. View Article : Google Scholar : PubMed/NCBI
15	Yoneda T, Williams P, Rhine C, Boyce BF, Dunstan C and Mundy GR: Suramin suppresses hypercalcemia and osteoclastic bone resorption in nude mice bearing a human squamous cancer. Cancer Res. 55:1989–1993. 1995.PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
17	Hofbauer LC, Neubauer A and Heufelder AE: Receptor activator of nuclear factor-kappa B ligand and osteoprotegerin: Potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer. 92:460–470. 2001. View Article : Google Scholar : PubMed/NCBI
18	Blair JM, Zheng Y and Dunstan CR: RANK ligand. Int J Biochem Cell Biol. 39:1077–1081. 2007. View Article : Google Scholar
19	Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR and de Crombrugghe B: The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 108:17–29. 2002. View Article : Google Scholar : PubMed/NCBI
20	Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, et al: Endocrine regulation of energy metabolism by the skeleton. Cell. 130:456–469. 2007. View Article : Google Scholar : PubMed/NCBI
21	Zoch ML, Clemens TL and Riddle RC: New insights into the biology of osteocalcin. Bone. 82:42–49. 2016. View Article : Google Scholar
22	Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY, Lian JB, Stein JL, Stein GS and van Wijnen AJ: The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts. J Biol Chem. 280:20274–20285. 2005. View Article : Google Scholar : PubMed/NCBI
23	Lian JB and Stein GS: Runx2/Cbfa1: A multifunctional regulator of bone formation. Curr Pharm Des. 9:2677–2685. 2003. View Article : Google Scholar : PubMed/NCBI
24	Karsenty G: Role of Cbfa1 in osteoblast differentiation and function. Semin Cell Dev Biol. 11:343–346. 2000. View Article : Google Scholar : PubMed/NCBI
25	Ducy P, Zhang R, Geoffroy V, Ridall AL and Karsenty G: Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation. Cell. 89:747–754. 1997. View Article : Google Scholar : PubMed/NCBI
26	Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, et al: Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 89:755–764. 1997. View Article : Google Scholar : PubMed/NCBI
27	Mackie EJ: Osteoblasts: Novel roles in orchestration of skeletal architecture. Int J Biochem Cell Biol. 35:1301–1305. 2003. View Article : Google Scholar : PubMed/NCBI
28	Harada S and Rodan GA: Control of osteoblast function and regulation of bone mass. Nature. 423:349–355. 2003. View Article : Google Scholar : PubMed/NCBI
29	Tingart M, Beckmann J, Opolka A, Matsuura M, Wiech O, Grifka J and Grässel S: Influence of factors regulating bone formation and remodeling on bone quality in osteonecrosis of the femoral head. Calcif Tissue Int. 82:300–308. 2008. View Article : Google Scholar : PubMed/NCBI
30	Weinstein RS, Jilka RL, Parfitt AM and Manolagas SC: Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest. 102:274–282. 1998. View Article : Google Scholar : PubMed/NCBI
31	Wyles CC, Houdek MT, Crespo-Diaz RJ, Norambuena GA, Stalboerger PG, Terzic A, Behfar A and Sierra RJ: Adipose-derived mesenchymal stem cells are phenotypically superior for regeneration in the setting of osteonecrosis of the femoral head. Clin Orthop Relat Res. 473(10): 3080–3090. 2015. View Article : Google Scholar : PubMed/NCBI
32	Gao YS and Zhang CQ: Comment on: Osteogenic abilities of bone marrow stromal cells are not defective in patients with osteonecrosis. Int Orthop. 34:457author reply 459. 2010. View Article : Google Scholar : PubMed/NCBI
33	Teitelbaum SL: Bone resorption by osteoclasts. Science. 289:1504–1508. 2000. View Article : Google Scholar : PubMed/NCBI
34	Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F and Heymann D: The molecular triad OPG/RANK/RANKL: Involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 15:457–475. 2004. View Article : Google Scholar : PubMed/NCBI
35	Yamada Y, Ando F, Niino N and Shimokata H: Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men. Mol Genet Metab. 80:344–349. 2003. View Article : Google Scholar : PubMed/NCBI
36	Gori F, Hofbauer LC, Dunstan CR, Spelsberg TC, Khosla S and Riggs BL: The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated. Endocrinology. 141:4768–4776. 2000.PubMed/NCBI
37	Grässel S, Beckmann J, Rath B, Vogel M, Grifka J and Tingart M: Expression profile of matrix metalloproteinase-2 and -9 and their endogenous tissue inhibitors in osteonecrotic femoral heads. Int J Mol Med. 26:127–133. 2010. View Article : Google Scholar : PubMed/NCBI