The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker

详细信息    查看全文

• 作者：Gian Paolo Fadini (1) (2)
  Mattia Albiero (2)
  Renato Millioni (1) (3)
  Nicol Poncina (1) (2)
  Mauro Rigato (1)
  Rachele Scotton (1)
  Federico Boscari (1)
  Enrico Brocco (4)
  Giorgio Arrigoni (3) (5)
  Gianmarco Villano (1)
  Cristian Turato (1)
  Alessandra Biasiolo (1)
  Patrizia Pontisso (1)
  Angelo Avogaro (1) (2)
  
• 关键词：Animal models ; Biomarkers ; Chronic ulcers ; Pathogenesis ; Proteomics
• 刊名：Diabetologia
• 出版年：2014
• 出版时间：September 2014
• 年：2014
• 卷：57
• 期：9
• 页码：1947-1956
• 全文大小：503 KB
• 参考文献：1. Seshasai SR, Kaptoge S, Thompson A et al (2011) Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 364:829-41 CrossRef
  2. Morbach S, Furchert H, Groblinghoff U et al (2012) Long-term prognosis of diabetic foot patients and their limbs: amputation and death over the course of a decade. Diabetes Care 35:2021-027 CrossRef
  3. Schaper NC, Apelqvist J, Bakker K (2012) Reducing lower leg amputations in diabetes: a challenge for patients, healthcare providers and the healthcare system. Diabetologia 55:1869-872 CrossRef
  4. Gary Sibbald R, Woo KY (2008) The biology of chronic foot ulcers in persons with diabetes. Diabetes Metab Res Rev 24(Suppl 1):S25–S30 CrossRef
  5. Clark RA (1985) Cutaneous tissue repair: basic biologic considerations. I. J Am Acad Dermatol 13:701-25 CrossRef
  6. Broughton G 2nd, Janis JE, Attinger CE (2006) The basic science of wound healing. Plast Reconstr Surg 117:12S-4S CrossRef
  7. American Diabetes Association (1999) Consensus Development Conference on Diabetic Foot Wound Care: 7-8 April 1999, Boston, Massachusetts. Diabetes Care 22:1354-360 CrossRef
  8. Kussmann M, Raymond F, Affolter M (2006) OMICS-driven biomarker discovery in nutrition and health. J Biotechnol 124:758-87 CrossRef
  9. Gjesing AP, Pedersen O (2012) ‘Omics-driven discoveries in prevention and treatment of type 2 diabetes. Eur J Clin Invest 42:579-88 CrossRef
  10. Eming SA, Koch M, Krieger A et al (2010) Differential proteomic analysis distinguishes tissue repair biomarker signatures in wound exudates obtained from normal healing and chronic wounds. J Proteome Res 9:4758-766 CrossRef
  11. Krisp C, Jacobsen F, McKay MJ et al (2013) Proteome analysis reveals antiangiogenic environments in chronic wounds of diabetes mellitus type 2 patients. Proteomics 13:2670-681 CrossRef
  12. Sweitzer SM, Fann SA, Borg TK, Baynes JW, Yost MJ (2006) What is the future of diabetic wound care? Diabetes Educ 32:197-10 CrossRef
  13. Ross PL, Huang YN, Marchese JN et al (2004) Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics 3:1154-169 CrossRef
  14. da Huang W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44-7 CrossRef
  15. Turato C, Biasiolo A, Pengo P et al (2011) Increased antiprotease activity of the SERPINB3 polymorphic variant SCCA-PD. Exp Biol Med (Maywood) 236:281-90 CrossRef
  16. Villano G, Quarta S, Ruvoletto MG et al (2010) Role of squamous cell carcinoma antigen-1 on liver cells after partial hepatectomy in transgenic mice. Int J Mol Med 25:137-43
  17. Fadini GP, Albiero M, Menegazzo L et al (2010) The redox enzyme p66Shc contributes to diabetes and ischemia-induced delay in cutaneous wound healing. Diabetes 59:2306-314 CrossRef
  18. Mehta TS, Zakharkin SO, Gadbury GL, Allison DB (2006) Epistemological issues in omics and high-dimensional biology: give the people what they want. Physiol Genomics 28:24-2 CrossRef
  19. Kirk P, Witkover A, Bangham CR et al (2013) Balancing the robustness and predictive performance of biomarkers. J Comput Biol 20:979-89 CrossRef
  20. Gatto M, Iaccarino L, Ghirardello A et al (2013) Serpins, immunity and autoimmunity: old molecules, new functions. Clin Rev Allergy Immunol 45:267-80 CrossRef
  21. Quarta S, Vidalino L, Turato C et al (2010) SERPINB3 induces epithelial-mesenchymal transition. J Pathol 221:343-56 CrossRef
  22. Villano G, Lunardi F, Turato C et al (2012) Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure. Exp Biol Med (Maywood) 237:1474-482 CrossRef
  23. Vidalino L, Doria A, Quarta S et al (2009) SERPINB3, apoptosis and autoimmunity. Autoimmun Rev 9:108-12 CrossRef
  24. Villano G, Ruvoletto M, Ceolotto G et al (2013) SERPINB3 is associated with longer survival in transgenic mice. Sci Rep 3:3056 CrossRef
  25. Dinh T, Tecilazich F, Kafanas A et al (2012) Mechanisms involved in the development and healing of diabetic foot ulceration. Diabetes 61:2937-947 CrossRef
  26. Menghini R, Uccioli L, Vainieri E et al (2013) Expression of tissue inhibitor of metalloprotease 3 is reduced in ischemic but not neuropathic ulcers from patients with type 2 diabetes mellitus. Acta Diabetol 50:907-10 CrossRef
  27. Schwanhausser B, Busse D, Li N et al (2011) Global quantification of mammalian gene expression control. Nature 473:337-42 CrossRef
  28. Hamanaka S, Ujihara M, Numa F, Kato H (1997) Serum level of squamous cell carcinoma antigen as a new indicator of disease activity in patients with psoriasis. Arch Dermatol 133:393-95 CrossRef
  
• 作者单位：Gian Paolo Fadini (1) (2)
  Mattia Albiero (2)
  Renato Millioni (1) (3)
  Nicol Poncina (1) (2)
  Mauro Rigato (1)
  Rachele Scotton (1)
  Federico Boscari (1)
  Enrico Brocco (4)
  Giorgio Arrigoni (3) (5)
  Gianmarco Villano (1)
  Cristian Turato (1)
  Alessandra Biasiolo (1)
  Patrizia Pontisso (1)
  Angelo Avogaro (1) (2)
  
  1. Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy
  2. Venetian Institute of Molecular Medicine, Padova, Padova, Italy
  3. Proteomic Center of Padova, University of Padova, Padova, Italy
  4. Foot and Ankle Clinic, Policlinico di Abano Terme, Abano Terme, PD, Italy
  5. Department of Biomedical Sciences, University of Padova, Via U. Bassi 58/B, 35131, Padova, Italy
  
• ISSN：1432-0428

文摘

Aims/hypothesis Chronic foot ulceration is a severe complication of diabetes, driving morbidity and mortality. The mechanisms underlying delaying wound healing in diabetes are incompletely understood and tools to identify such pathways are eagerly awaited. Methods Wound biopsies were obtained from 75 patients with diabetic foot ulcers. Matched subgroups of rapidly healing (RH, n--7) and non-healing (NH, n--1) patients were selected. Proteomic analysis was performed by labelling with isobaric tag for relative and absolute quantification and mass spectrometry. Differentially expressed proteins were analysed in NH vs RH for identification of pathogenic pathways. Individual sample gene/protein validation and in vivo validation of candidate pathways in mouse models were carried out. Results Pathway analyses were conducted on 92/286 proteins that were differentially expressed in NH vs RH. The following pathways were enriched in NH vs RH patients: apoptosis, protease inhibitors, epithelial differentiation, serine endopeptidase activity, coagulation and regulation of defence response. SerpinB3 was strongly upregulated in RH vs NH wounds, validated as protein and mRNA in individual samples. To test the relevance of serpinB3 in vivo, we used a transgenic mouse model with α1-antitrypsin promoter-driven overexpression of human SERPINB3. In this model, wound healing was unaffected by SERPINB3 overexpression in non-diabetic or diabetic mice with or without hindlimb ischaemia. In an independent validation cohort of 47 patients, high serpinB3 protein content was confirmed as a biomarker of healing improvement. Conclusions/interpretation We provide a benchmark for the unbiased discovery of novel molecular targets and biomarkers of impaired diabetic wound healing. High serpinB3 protein content was found to be a biomarker of successful healing in diabetic patients.