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Proof of Concept on Functionality Improvement of Mesenchymal Stem-Cells, in Postmenopausal Osteoporotic Women Treated with Teriparatide (PTH1-34), After Suffering Atypical Fractures

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Abstract

Osteoporosis long-term treatment with nitrogen-containing bisphosphonates, has been associated with uncommon adverse effects, as atypical femoral fractures (AFF). Thus, treatment with teriparatide (TPTD; fragment of human parathyroid hormone; PTH1−34) has been proposed for such patients. Besides its anabolizing effect on bone, TPTD may affect stem-cell mobilization and expansion. Bone marrow mononuclear cells (BMMNC) were isolated from five women that had suffered AFF associated to bisphosphonate treatment, before and after 6 months of TPTD therapy. The presence of mesenchymal stromal cells (CD73, CD90 and CD105 positive cells), gene expression of NANOG, SOX2 and OCT4, proliferation, senescence and capacity to differentiate into osteoblasts and adipocytes were analyzed. After TPTD treatment, BMMNC positive cells for CD73, CD90 and CD105 increased from 6.5 to 37.5% (p < 0.05); NANOG, SOX2 and OCT4 were upregulated, being statistically significant for NANOG (p < 0.05), and cells increased proliferative capacity more than 50% at day 7 (p < 0.05). Senescence was reduced 2.5-fold (p < 0.05), increasing differentiation capacity into osteoblasts and adipocytes, with more than twice mineralization capacity of extracellular matrix or fat-droplet formation (p < 0.05), respectively. Results show that TPTD treatment caused BMMNC “rejuvenation”, increasing the number of cells in a more undifferentiated stage, with higher differentiation potency. This effect may favor TPTD anabolic action on bone in such patients with AFF, increasing osteoblast precursor cells. Such response could also arise in other osteoporotic patients treated with TPTD, without previous AFF. Furthermore, our data suggest that TPTD effect on stromal cells may have clinical implications for bone-regenerative medicine. Further studies may deepen on this potential.

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Acknowledgements

We acknowledge all of the funding sources.

Funding

Supported by Grants AGL2013-45110-R of “Ministerio de Ciencia e Innovación” (MICINN); PI081692 and PI15/01857 “Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad” (RETICEF) and CIBER “Fragilidad y Envejecimiento Saludable” (CIBERFES) of “Instituto de Salud Carlos III” (ISCIII), “Ministerio de Economía y Competitividad” (MINECO) and European Union (EU); and “Ayudas de Intensificación de la Investigación” and “Grupo CTS413” of “Junta de Andalucía”, Spain.

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Authors and Affiliations

  1. Unidad de Gestión Clínica de Endocrinología y Nutrición, CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, RETICEF, 14004, Córdoba, Spain

    Antonio Casado-Díaz & José Manuel Quesada-Gómez

  2. Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, RETICEF CIBERFES, 14071, Córdoba, Spain

    Gabriel Dorado

  3. Dep. de Medicina Interna, Dept. de Histología y Citología Normal y Patológica, Escuela de Medicina, Unidad de Metabolismo óseo, Hospital Universitario Virgen Macarena, Universidad de Sevilla, RETICEF, 41009, Seville, Spain

    Mercè Giner

  4. Dept. de Medicina, Escuela de Medicina, Universidad de Sevilla, RETICEF, 41009, Seville, Spain

    María José Montoya

  5. Unidad de Gestión Clínica de Cardiología, Hospital Universitario Virgen de Valme, 41014, Seville, Spain

    Cristina Navarro-Valverde

  6. Instituto Hospital del Mar de Investigaciones Médicas (IMIM), Universitat Autònoma de Barcelona, RETICEF, CIBERFES, 08003, Barcelona, Spain

    Adolfo Díez-Pérez

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  1. Antonio Casado-Díaz
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  2. Gabriel Dorado
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  3. Mercè Giner
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  7. José Manuel Quesada-Gómez
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Contributions

ACD, GD and JMQG conceived and designed the experiments. ACD, MG, MJM and CNV performed the experiments. ACD, ADP and JMQG contributed with analysis tools and patients data. ACD, GD and JMQG wrote the paper. All authors analyzed and interpreted the data. JMQG is guarantor.

Corresponding author

Correspondence to José Manuel Quesada-Gómez.

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Conflict of interest

Antonio Casado-Díaz, Gabriel Dorado, Mercè Giner, María José Montoya, Cristina Navarro-Valverde, Adolfo Díez-Pérez, José Manuel Quesada-Gómez declare no conflict of interest.

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Patients signed informed consent, in accordance with regulations of the Clinical Research Ethics Committee of Parc de Salut Mar, which approved the study. This was carried out in accordance with the terms of the Declaration of Helsinki.

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Casado-Díaz, A., Dorado, G., Giner, M. et al. Proof of Concept on Functionality Improvement of Mesenchymal Stem-Cells, in Postmenopausal Osteoporotic Women Treated with Teriparatide (PTH1-34), After Suffering Atypical Fractures. Calcif Tissue Int 104, 631–640 (2019). https://doi.org/10.1007/s00223-019-00533-0

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