STAT1-caspase 3 pathway in the apoptotic process associated with steroid-induced necrosis of the femoral head
Tóm tắt
Osteocyte apoptosis is the main manifestation of steroid-induced avascular necrosis of the femoral head (SANFH). STAT1 and caspase 3 participate in the process of apoptosis and STAT1 upregulates the expression of caspase 3. We examined the relationship between the STAT1-caspase 3 pathway and apoptosis in SANFH. All specimens were divided into four groups: the negative control group, Ficat I–II group, Ficat III group, and Ficat IV–V group, and examined histologically, with a TUNEL assay, immunohistochemically, with a caspase 3 activity assay, with ELISAs of STAT1 and phospo-STAT1 (p-STAT1), with a western blotting analysis of p-STAT1 and with real-time RT-PCR. The proportion of empty lacunae increased significantly with the development of SANFH. The proportion of TUNEL-positive cells and immunohistochemical analysis of caspase 3 also increased significantly, although the Ficat I–II group did not differ significantly from the negative control group. Immunohistochemical analysis of STAT1 and p-STAT1, caspase 3 activity all showed significant differences among the groups. An ELISA and a western blotting analysis of p-STAT1 showed significant differences among the groups. An ELISA of STAT1, real-time RT-PCR analysis of caspase 3 and STAT1 all showed significant differences among the groups except between the Ficat I–II and negative control groups. The correlation analysis showed strong positive relationships between the proportion of empty lacunae and the proportion of TUNEL-positive cells between caspase 3 activity and the proportion of TUNEL-positive cells and between the levels of p-STAT1 protein and caspase 3 mRNA. The apoptotic process in SANFH develops with the upregulated expression of caspase 3 via the expression and activation of STAT1. The STATI-caspase 3 pathway plays a critical role in the development of SANFH.
Tài liệu tham khảo
Abdi A, Sadraie H, Dargahi L, Khalaj L, Ahmadiani A (2011) Apoptosis inhibition can be threatening in Abeta-induced neuroinflammation, through promoting cell proliferation. Neurochem Res 36(1):39–48
Assouline-Dayan Y, Chang C, Greenspan A et al (2002) Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 32(2):94–124
Boumpas DT, Chrousos GP, Wilder RL et al (1993) Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 119(12):1198–1208
Calder JDF, Buttery L, Revell PA et al (2004) Apoptosis—a significant cause of bone cell death in osteonecrosis of the femoral head. J Bone Joint Surg Br 86(8):1209–1213
Chua CC, Chua BHL, Chen Z et al (2003) Dexamethasone induces caspase activation in murine osteoblastic MC3T3-E1 cells. Biochim Biophys Acta (BBA) Mol Cell Res 1642(1):79–85
Cruess RL, Ross D, Crawshaw E (1975) The etiology of steroid-induced avascular necrosis of bone: a laboratory and clinical study. Clin Orthop Relat Res 113:178–183
Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. In: Science-AAAS-weekly paper edition-including guide to scientific information, vol 264, pp 1415–1420
Dedoni S, Olianas MC, Onali P (2010) Interferon-β induces apoptosis in human SH-SY5Y neuroblastoma cells through activation of JAK–STAT signaling and down-regulation of PI3K/Akt pathway. J Neurochem 115(6):1421–1433
Dempster DW, Moonga BS, Stein LS et al (1997) Glucocorticoids inhibit bone resorption by isolated rat osteoclasts by enhancing apoptosis. J Endocrinol 154(3):397–406
Doeppner TR, Bretschneider E, Doehring M et al (2011) Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia. Acta Neuropathol 122(4):429–442
Eberhardt AW, Yeager-Jones A, Blair HC (2001) Regional trabecular bone matrix degeneration and osteocyte death in femora of glucocorticoid-treated rabbits. Endocrinology 142(3):1333–1340
Ficat RP (1985) Idiopathic bone necrosis of the femoral head. J Bone Joint Surg [Br] 67(1):3–9
Gu G, Hentunen TA, Nars M et al (2005) Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis. Apoptosis 10(3):583–595
Hock JM, Krishnan V, Onyia JE et al (2001) Osteoblast apoptosis and bone turnover. J Bone Miner Res 16(6):975–984
James J, Steijn-Myagkaya GL (1986) Death of osteocytes: electron microscopy after in vitro ischaemia. J Bone Joint Surg 68(4):620–624
Koo KH, Kim R, Kim YS et al (2002) Risk period for developing osteonecrosis of the femoral head in patients on steroid treatment. Clin Rheumatol 21(4):299–303
Kostanian IA, Vonarshenko AV, Lipkin VM (2010) STAT1: a many-sided transcription factor. Bioorg Khim 36(1):15
Kumar A, Commane M, Flickinger TW et al (1997) Defective TNF-α-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 278(5343):1630–1632
Liu Y, Porta A, Peng X et al (2004) Prevention of glucocorticoid-induced apoptosis in osteocytes and osteoblasts by calbindin-D28k. J Bone Miner Res 19(3):479–490
Mitchell MD, Kundel HL, Steinberg ME et al (1986) Avascular necrosis of the hip: comparison of MR, CT, and scintigraphy. Am J Roentgenol 147(1):67–71
Murata M, Kumagai K, Miyata N et al (2007) Osteonecrosis in stroke-prone spontaneously hypertensive rats: effect of glucocorticoid. J Orthop Sci 12(3):289–295
Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6(2):99
Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407(6805):784–788
Sharif M, Whitehouse A, Sharman P et al (2004) Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and expression of caspase-3. Arthritis Rheum 50(2):507–515
Sironi JJ, Ouchi T (2004) STAT1-induced apoptosis is mediated by caspases 2, 3, and 7. J Biol Chem 279(6):4066–4074
Tajima K, Takaishi H, Takito J et al (2010) Inhibition of STAT1 accelerates bone fracture healing. J Orthop Res 28(7):937–941
Wagner M, Siddiqui MA (2009) Signaling networks regulating cardiac myocyte survival and death. Curr Opin Investig Drugs (Lond, England: 2000) 10(9):928
Weinstein RS, Manolagas SC (2005) Apoptosis in glucocorticoid-induced bone disease. Curr Opin Endocrinol Diabetes Obes 12(3):219–223
Weinstein RS, Jilka RL, Parfitt AM et al (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Investig 102(2):274
Weinstein RS, Nicholas RW, Manolagas SC (2000) Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85(8):2907–2912
Yong W, Chunjin G, Baosen P et al (2008) The changes in coagulation–fibrinolysis systems in rabbits with steroid-induced avascular necrosis of the femoral head. J Cap Med Univ 3:016
Zadegan F, Raould A, Bizot P et al (2008) Osteonecrosis after allogeneic bone marrow transplantation. Clin Orthop Relat Res 466(2):287–293
Zhang J, Mikecz K, Finnegan A et al (2000) Spontaneous thymocyte apoptosis is regulated by a mitochondrion-mediated signaling pathway. J Immunol 165(6):2970–2974