Download PDF
Osteologie 2015; 24(02): 99-106
DOI: 10.1055/s-0037-1622045
Original and review articles
Schattauer GmbH

Effects of urocortin on spine?

Results from the rat osteopenia modelEffekte von Urocortin auf die Wirbelsäule?Ergebnisse im Ratten-Osteopeniemodell
S. Sehmisch
1   Department of Trauma and Reconstructive Surgery, University Medical Center, Goettingen, Germany
,
M. Komrakova
1   Department of Trauma and Reconstructive Surgery, University Medical Center, Goettingen, Germany
,
L. Kottwitz
1   Department of Trauma and Reconstructive Surgery, University Medical Center, Goettingen, Germany
,
C. Dullin
2   Department of Radiology, University Medical Center, Goettingen, Germany
,
U. Schmelz
3   Medical Institute of General Hygiene and Environmental Health, University Medical Center, Goettingen, Germany
,
K. M. Stuermer
1   Department of Trauma and Reconstructive Surgery, University Medical Center, Goettingen, Germany
,
M. Tezval
1   Department of Trauma and Reconstructive Surgery, University Medical Center, Goettingen, Germany
› Author Affiliations
Further Information

Publication History

received: 26 March 2014

accepted after revision: 25 November 2014

Publication Date:
02 January 2018 (online)

Also available at
    Permissions and Reprints

Summary

Introduction

Urocortin (UCN) is a member of the cortico tropin-releasing factor family. UCN enhances osteoblast differentiation and inhibits osteoclasts in vitro. In the present study, the effect of UCN on spine was assessed in the rat osteopenia model.

Material and methods

Sprague Dawley rats (3 month old) were either ovariectomized (OVX, n = 48) or sham operated (n = 12). After 9 weeks, OVX rats were divided into 4 groups (n = 12): OVX, UCN low (3 µ/kg BW), UCN high (30 µ/kg BW), estradiol-17β-benzoate (0.2 mg/kg BW). UCN was administered daily s. c., estrogen was supplied with food for 35 d. Thereafter, the lumbar vertebral bodies were analyzed by biomechanical test, micro-CT, pQCT, gene expression and ashing analyses. Serum alkaline phosphatase (AP), beta-Crosslaps, calcium, leptin levels were assessed.

Results

Stiffness, BMD, BV/TV, trabecular parameters improved in UCN high group. UCN low dose had less effect on spine. AP was enhanced in UCN high group, leptin increased in both UCN groups, other serum parameters and expression of bone genes did not change. UCN high dose showed osteoprotective effect in spine.

Discussion

Further studies are needed to understand mechanism of UCN action on bone and to reveal potential side effects.

Zusammenfassung

Einleitung

Urocortin (UCN) gehört zur Corticotropin- Releasing Faktor Familie. In vitro wurde nach UCN-Therapie eine verstärkte Differenzierung von Osteoblasten sowie eine Hemmung von Osteoklasten beobachtet. In der vorliegenden Studie wurde der Effekt von UCN an der Wirbelsäule in einem Ratten-Osteopeniemodell untersucht.

Material und Methoden

Sprague-Dawley-Ratten (3 Monate alt) wurden entweder ovariektomiert (OVX, n = 48) oder scheinoperiert (n = 12). Nach neun Wochen wurden die OVX-Ratten in vier Gruppen (n = 12) aufgeteilt: OVX, UCN low (3 µ/kg KG), UCN high (30 µ/kg KG), Östradiol-17β-benzoat (0,2 mg/kg KG). UCN wurde täglich s. c. und Östrogen oral mit dem Futter über 35 d verabreicht. Danach wurden die Lendenwirbelkörper durch einen biomechanischen Test, Mikro-CT, pQCT, Genexpression und Veraschung analysiert. Im Serum wurde alkalische Phosphatase (AP), beta-Crosslaps, Kalzium und Leptin gemessen.

Ergebnisse

Sowohl die Bio mechanik als auch die Knochenmorphologie waren nach Therapie mit UCN in der hohen Dosierung verbessert. Die niedrigere UCN-Dosierung hat keine Effekte auf die Wirbelsäule. Es zeigten sich nach UCN-Therapie in höherer Dosierung deutlich osteoprotektive Effekte.

Diskussion

Weitere Studien sind notwendig, um den Mechanismus der UCN-Wirkung am Knochen zu verstehen und mögliche Nebenwirkungen zu zeigen.

Keywords

Urocortin - lumbar spine - ovariectomized rat - biomechanics

Schlüsselwörter

Urocortin - Lendenwirbel - Osteoporose - Biomechanik
 

  • References

  • 1 Vaughan J, Donaldson C, Bittencourt J. et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995; 378: 287-292.
    CrossrefPubMedSearch in Google Scholar
  • 2 Fekete EM, Zorrilla EP. Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs. Front Neuroendocrinol 2007; 28: 1-27.
    CrossrefPubMedSearch in Google Scholar
  • 3 Hauger RL, Olivares-Reyes JA, Braun S. et al. Mediation of corticotropin releasing factor type 1 receptor phosphorylation and desensitization by protein kinase C: a possible role in stress adaptation. J Pharmacol Exp Ther 2003; 306: 794-803.
    CrossrefPubMedSearch in Google Scholar
  • 4 Onorati F, Chen-Scarabelli C, Knight R. et al. Targeting urocortin signaling pathways to enhance cardioprotection: is it time to move from bench to bedside?. Cardiovasc Drugs Ther 2013; 27: 451-463.
    CrossrefPubMedSearch in Google Scholar
  • 5 Tanaka M, Telegdy G. Antidepressant-like effects of the CRF family peptides, urocortin 1, urocortin 2 and urocortin 3 in a modified forced swimming test in mice. Brain Res Bull 2008; 75: 509-512.
    CrossrefPubMedSearch in Google Scholar
  • 6 Stengel A, Taché Y. CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress. Front Neurosci 2014; 18 (08) 52.
    Search in Google Scholar
  • 7 Brar BK, Stephanou A, Knight R. et al. Activation of protein kinase B/Akt by urocortin is essential for its ability to protect cardiac cells against hypoxia/reoxygenation-induced cell death. J Mol Cell Cardiol 2002; 34: 483-492.
    CrossrefPubMedSearch in Google Scholar
  • 8 Bale TL, Hoshijima M, Gu Y. et al. The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure. Proc Natl Acad Sci USA 2004; 101: 3697-3702.
    CrossrefPubMedSearch in Google Scholar
  • 9 Zhu H, Wang J, Li J, Li S. Corticotropin-releasing factor family and its receptors: pro-inflammatory or anti-inflammatory targets in the periphery?. Inflamm Res 2011; 60: 715-721.
    CrossrefPubMedSearch in Google Scholar
  • 10 Lohmann R, Frerichmann U, Stöckle U. et al. Proximal femoral fractures in the elderly. Analysis of data from health insurance providers on more than 23 million insured persons-part 1. Unfallchirurg 2007; 110: 603-609.
    PubMedSearch in Google Scholar
  • 11 Tezval M, Hansen S, Schmelz U. et al. Effect of Urocortin on strength and microarchitecture of osteopenic rat femur. J Bone Miner Metab. 2014 Mar 16. [Epub ahead of print].
    PubMedSearch in Google Scholar
  • 12 Combs CE, Fuller K, Kumar H. et al. Urocortin is a novel regulator of osteoclast differentiation and function through inhibition of a canonical transient receptor potential 1-like cation channel. J Endocrinol 2012; 212: 187-197.
    CrossrefPubMedSearch in Google Scholar
  • 13 Tezval M, Tezval H, Dresing K. et al. Differentiation dependent expression of urocortin’s mRNA and peptide in human osteoprogenitor cells: influence of BMP-2, TGF-beta-1 and dexamethasone. J Mol Histol 2009; 40: 331-341.
    CrossrefPubMedSearch in Google Scholar
  • 14 Gonzalez-Rey E, Chorny A, Varela N. et al. Therapeutic Effect of Urocortin on Collagen-Induced Arthritis by Down-Regulation of Inflammatory and Th1 Responses and Induction of Regulatory T Cells. Arthritis Rheum 2007; 56: 531-543.
    CrossrefPubMedSearch in Google Scholar
  • 15 Wronski TJ, Lowry PL, Walsh CC. et al. Skeletal alterations in ovariectomized rats. Calcif Tiss Int 1985; 37: 324-328.
    CrossrefPubMedSearch in Google Scholar
  • 16 Thompson DD, Simmons HA, Pirie CM. et al. Guidelines and animal models for osteoporosis. Bone 1995; 17: 125-133.
    Search in Google Scholar
  • 17 Sehmisch S, Erren M, Rack T. et al. Short-term effects of parathyroid hormone on rat lumbar vertebrae. Spine (Phila Pa 1976) 2009; 34: 2014-2021.
    CrossrefPubMedSearch in Google Scholar
  • 18 Stürmer EK, Seidlová-Wuttke D, Sehmisch S. et al. Standardized bending and breaking test for the normal and osteoporotic metaphyseal tibias of the rat: effect of estradiol, testosterone, and raloxifene. J Bone Miner Res 2006; 21: 89-96.
    PubMedSearch in Google Scholar
  • 19 Parfitt AM, Drezner MK, Glorieux FH. et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 1987; 02: 595-610.
    Search in Google Scholar
  • 20 Bouxsein ML, Boyd SK, Christiansen BA. et al. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res 2010; 25: 1468-1486.
    CrossrefPubMedSearch in Google Scholar
  • 21 Komrakova M, Stuermer EK, Werner C. et al. Effect of human parathyroid hormone hPTH (1-34) applied at different regimes on fracture healing and muscle in ovariectomized and healthy rats. Bone 2010; 47: 480-492.
    CrossrefPubMedSearch in Google Scholar
  • 22 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-L)L)CT method. Methods 2001; 25: 402-408.
    CrossrefPubMedSearch in Google Scholar
  • 23 Carlson KW, Nawy SS, Wei ET. et al. Inhibition of mouse melanoma cell proliferation by corticotropin-releasing hormone and its analogs. Anticancer Res 2001; 21: 1173-1179.
    Search in Google Scholar
  • 24 Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner 1991; 15: 175-192.
    CrossrefPubMedSearch in Google Scholar
  • 25 Komrakova M, Werner C, Wicke M. et al. Effect of daidzein, 4-methylbenzylidene camphor or estrogen on gastrocnemius muscle of osteoporotic rats undergoing tibia healing period. J Endocrinol 2009; 201: 253-262.
    CrossrefPubMedSearch in Google Scholar
  • 26 Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011; 377: 1276-1287.
    CrossrefPubMedSearch in Google Scholar
  • 27 Dempster DW, Zhou H. Chapter 22: New concepts in bone remodelling. In: Seibel MJ, Robins SP, Bilezikian JP. eds. Dynamics of Bone and Cartilage Metabolism: Principles and Clinical Applications. London/Oxford: Academic Press Elsevier; 2006: 377-389.
    Search in Google Scholar
  • 28 Väänänen HK, Härkönen PL. Estrogen and bone metabolism. Maturitas 1996; 23: S65-S69.
    CrossrefPubMedSearch in Google Scholar
  • 29 Kohno M, Kawahito Y, Tsubouchi Y. et al. Urocortin expression in synovium of patients with rheumatoid arthritis and osteoarthritis: relation to inflammatory activity. J Clin Endocrinol Metab 2001; 86: 4344-4352.
    CrossrefPubMedSearch in Google Scholar
  • 30 Spelsberg TC, Subramaniam M, Riggs BL. et al. The actions and interactions of sex steroids and growth factors/cytokines on the skeleton. Mol Endocrinol 1999; 13: 819-928.
    CrossrefPubMedSearch in Google Scholar
  • 31 Siggelkow H, Eidner T, Lehmann G. et al. Cytokines, osteoprotegerin, and RANKL in vitro and histomorphometric indices of bone turnover in patients with different bone diseases. J Bone Miner Res 2003; 18: 529-538.
    CrossrefPubMedSearch in Google Scholar
  • 32 Magni P, Dozio E, Galliera E. et al. Molecular aspects of adipokine-bone interactions. Curr Mol Med 2010; 10: 522-532.
    PubMedSearch in Google Scholar
  • 33 Cole JH, van der Meulen MC. Whole bone mechanics and bone quality. Clin Orthop Relat Res 2011; 469: 2139-2149.
    CrossrefPubMedSearch in Google Scholar
  • 34 Reid IR. Relationships between fat and bone. Osteoporos Int 2008; 19: 595-606.
    CrossrefPubMedSearch in Google Scholar
  • 35 Cirmanová V, Bayer M, Stárka L. et al. The effect of leptin on bone: an evolving concept of action. Physiol Res 2008; 57: 143-151.
    Search in Google Scholar
  • 36 Holloway WR, Collier FM, Aitken CJ. et al. Leptin inhibits osteoclast generation. J Bone Miner Res 2002; 17: 200-209.
    CrossrefPubMedSearch in Google Scholar
  • 37 Thomas T. The complex effects of leptin on bone metabolism through multiple pathways. Curr Opin Pharmacol 2004; 04: 295-300.
    CrossrefPubMedSearch in Google Scholar
  • 38 Kotz CM, Wang C, Levine AS. et al. Urocortin in the hypothalamic PVN increases leptin and affects uncoupling proteins-1 and -3 in rats. Am J Physiol Regul Integr Comp Physiol 2002; 282: R546-R551.
    CrossrefPubMedSearch in Google Scholar
  • 39 Turner RT, Vandersteenhoven JJ, Bell NH. The effects of ovariectomy and 17 beta-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res 1987; 02: 115-122.
    Search in Google Scholar
  • 40 Komrakova M, Stuermer EK, Sturm A. et al. Efficiency of 48h vs. 24h injection of parathyroid hormone for amelioration of osteopenic spine properties in male rats. The Open Bone J 2012; 04: 20-26.
    Search in Google Scholar
  • 41 Davidson SM, Rybka AE, Townsend PA. The powerful cardioprotective effects of urocortin and the corticotropin releasing hormone (CRH) family. Biochem Pharmacol 2009; 77 (02) 141-150.
    CrossrefPubMedSearch in Google Scholar
  • 42 Davis ME, Pemberton CJ, Yandle TG. et al. Urocortin 2 infusion in healthy humans: hemodynamic, neurohormonal, and renal responses. J Am Coll Cardiol 2007; 49 (04) 461-471.
    CrossrefPubMedSearch in Google Scholar
  • 43 Lei Z, Xiaoying Z, Xingguo L. Ovariectomyassociated changes in bone mineral density and bone marrow haematopoiesis in rats. Int J Exp Pathol 2009; 90: 512-519.
    CrossrefPubMedSearch in Google Scholar