Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Dec 26, 2020; 12(12): 1667-1690
Published online Dec 26, 2020. doi: 10.4252/wjsc.v12.i12.1667
Effects of normobaric cyclic hypoxia exposure on mesenchymal stem-cell differentiation–pilot study on bone parameters in elderly
Marta Camacho-Cardenosa, José Manuel Quesada-Gómez, Alba Camacho-Cardenosa, Alejo Leal, Gabriel Dorado, Bárbara Torrecillas-Baena, Antonio Casado-Díaz
Marta Camacho-Cardenosa, Alba Camacho-Cardenosa, Facultad Ciencias del Deporte, Universidad De Extremadura, Cáceres 10003, Spain
José Manuel Quesada-Gómez, Bárbara Torrecillas-Baena, Antonio Casado-Díaz, CIBER De Fragilidad Y Envejecimiento Saludable (CIBERFES), Unidad De Gestión Clínica De Endocrinología Y Nutrición, Instituto Maimónides De Investigación Biomédica De Córdoba, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
Alejo Leal, Servicio de Traumatología, Hospital de Cáceres, Cáceres 10004, Spain
Gabriel Dorado, Departamento Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba-CIBERFES, 14071 Córdoba, Spain
Author contributions: Camacho-Cardenosa M, Casado-Díaz A and Quesada-Gómez JM conceived and designed the experiments; Camacho-Cardenosa M, Torrecillas-Baena B and Casado-Díaz A performed the experiments in vitro; Camacho-Cardenosa M, Camacho-Cardenosa A and Leal A performed the studies with the elderly volunteers; Camacho-Cardenosa M, Casado-Díaz A, Dorado G and Quesada-Gómez JM wrote the paper. All authors analyzed and interpreted the data.
Supported by Government of Extremadura GAEDAF Research Group, No. GR18003; Ministerio de Educación, Cultura y Deporte, No. FPU15/00452; and Instituto de Salud Carlos III, No. PI15/01857 and No. PI18/01659.
Institutional review board statement: The study was approved by the Bioethical and Biosecurity Commission of the University of Extremadura (17/2016).
Conflict-of-interest statement: The authors have nothing to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Marta Camacho-Cardenosa, PhD, Postdoc, Facultad Ciencias Del Deporte, Universidad De Extremadura, Av. Universidad, s/n, Cáceres 10003, Spain. mcamachocardenosa@unex.es
Received: September 3, 2020
Peer-review started: September 3, 2020
First decision: September 15, 2020
Revised: September 30, 2020
Accepted: October 20, 2020
Article in press: October 20, 2020
Published online: December 26, 2020
ARTICLE HIGHLIGHTS
Research background

Bone mass and strength decline with aging. Mesenchymal stem cells (MSC) are precursors of osteoblasts and adipocytes. Osteoblastogenesis decreases, and adipogenesis increases, in bone-marrow MSC with aging. Receptor activator for nuclear factor kappa B ligand (RANKL) induces osteoclastogenesis, whereas Osteoprotegerin (OPG) represses it. Therefore, the OPG/RANKL ratio regulates bone resorption. Hypoxia induces the HIF-1A gene, encoding a transcription factor which regulates, among others, genes involved in angiogenesis and osteogenesis. Chronic hypoxia has negative effects on bone. Yet, cyclic exposure to hypoxia for short periods, followed by long times in normoxia, may have beneficial effects.

Research motivation

Cyclic hypoxia can be a non-pharmacological method for the prevention and treatment of different clinical conditions, such as loss of bone mass with age.

Research objectives

Investigate the effects of cyclic hypoxia exposure on differentiation of human MSC, derived from bone-marrow, into osteoblasts or adipocytes. Conduct a pilot study on the cyclic hypoxia effect on bone-mineral density and fat mass in elderly.

Research methods

MSC were induced to differentiate into osteoblasts or adipocytes, in cyclic hypoxia (3% O2 for 1, 2 or 4 h, 4 d a week). Osteogenic and adipogenic markers were measured. In addition, elderly were exposed to either low oxygen concentration in air (simulating an altitude of 2500 m above sea level) in a hypoxia chamber, or to normoxia, for 18 wk (36 CH sessions of 16 min each). Percentages of fat mass and bone mineral-density from whole body, trunk and right proximal femur were assessed, using dual-energy X-ray absorptiometry.

Research results

Cyclic hypoxia with 4 h of hypoxia exposure inhibited osteogenesis and adipogenesis. Osteocalcin, vascular endothelial growth factor A and LRP (5/6)/ dickkopf-1 gene expressions were upregulated in osteoblasts. Yet, the latter decreased in adipocytes. Cyclic hypoxia treatments increased the OPG/RANKL ratio, in both cell types. Elderly exposed to cyclic hypoxia increased total bone mineral-density, although the percentage of fat did not vary between groups.

Research conclusions

Cyclic hypoxia affects MSC differentiation into osteoblasts or adipocytes. It can increase bone mass, by inhibiting osteoclastic activity, through upregulating the OPG/RANK ratio.

Research perspectives

The potential of using cyclic hypoxia to prevent and treat bone-mass loss associated with ageing is promising. Yet, its mechanisms of action need to be further explored. Trials with a larger number of participants should be carried out to evaluate different patterns and times of exposure to cyclic hypoxia.