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Reversal of Osteopenia in Ovariectomized Rats by Pentoxifylline: Evidence of Osteogenic and Osteo-Angiogenic Roles of the Drug

  • Subhashis Pal
  • Konica Porwal
  • Himalaya Singh
  • Mohd Yaseen Malik
  • Mamunur Rashid
  • Chirag Kulkarni
  • Yasir Khan
  • Kumaravelu Jagavelu
  • Muhammad Wahajuddin
  • Naibedya ChattopadhyayEmail author
Original Research
  • 28 Downloads

Abstract

Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor and is used for the management of intermittent claudication. We tested whether PTX has oral efficacy in stimulating new bone formation. Rat calvarial osteoblasts (RCO) were used to study the effect of PTX on osteoblast differentiation and angiogenesis. Pharmacokinetic and pharmacodynamic studies were carried out in rats to determine an oral dose of PTX. In ovariectomized (OVX) rats with osteopenia, the effect of PTX on various skeletal parameters was studied, and compared with teriparatide. Effect of PTX on angiogenic signaling was studied by immunoblotting and relevant pharmacologic inhibitors. Bone vascularity was measured by intravenous injection of polystyrene fluorospheres followed by in vivo imaging, and angiogenesis was studied in vitro by tubulogenesis of endothelial cells and in vivo by Matrigel plug assay. Effective concentration (EC50) of PTX in RCO was 8.2 nM and plasma PTX level was 7 nM/mL after single oral dosing of 25 mg/kg, which was 1/6th the clinically used dose. At this dose, PTX enhanced bone regeneration at femur osteotomy site and completely restored bone mass, microarchitecture, and strength in OVX rats. Furthermore, PTX increased surface referent bone formation parameters and serum bone formation marker (PINP) without affecting the resorption marker (CTX-1). PTX increased the expression of vascular endothelial growth factor and its receptor in bones and osteoblasts. PTX also increased skeletal vascularity, tubulogenesis of endothelial cells and in vivo angiogenesis. Taken together, our study suggested that PTX at 16% of adult human oral dose completely reversed osteopenia in OVX rats by osteogenic and osteo-angiogenic mechanisms.

Keywords

Pharmacokinetics Bone turnover Bone formation Osteopenia Vascularity Angiogenesis 

Notes

Acknowledgements

The authors are thankful for the technical assistance provided by Dr. Kavita Singh at the confocal facility of the Electron Microscopy Unit, Sophisticated Analytical Instrument Facility (SAIF), and Mr. Navodayam Kalleti, Division of Toxicology for assistance with In-Vivo Imaging System.

Funding

Council of Scientific and Industrial Research, Government of India to Naibedya Chattopadhyay.

Compliance with Ethical Standards

Conflict of interest

Subhashis Pal, Konica Porwal, Himalaya Singh, Mohd Yaseen Malik, Mamunur Rashid, Chirag Kulkarni, Yasir Khan, Kumaravelu Jagavelu, Muhammad Wahajuddin, and Naibedya Chattopadhyay declare that they have no conflict of Interest.

Human and Animal Rights and Informed Consent

All animal experimental procedures were prior approved (Institutional Animal Ethics Committee approval no. CDRI/IAEC/2015/131) and conducted as per the guidelines laid by the Committee for the Purpose of Control and Supervision of Experiments on Animals. This article does not contain any studies with human participants performed by any of the authors. Informed consent is not required.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Subhashis Pal
    • 1
  • Konica Porwal
    • 1
  • Himalaya Singh
    • 2
  • Mohd Yaseen Malik
    • 3
  • Mamunur Rashid
    • 3
  • Chirag Kulkarni
    • 1
  • Yasir Khan
    • 1
  • Kumaravelu Jagavelu
    • 2
  • Muhammad Wahajuddin
    • 3
  • Naibedya Chattopadhyay
    • 1
    Email author
  1. 1.Division of EndocrinologyCSIR-Central Drug Research Institute, Council of Scientific and Industrial ResearchLucknowIndia
  2. 2.Division of PharmacologyCSIR-CDRILucknowIndia
  3. 3.Division of PharmaceuticsCSIR-CDRILucknowIndia

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