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Released nucleotides acting via ionotropic P2X7 and metabotropic P2Y<jats:sub>6<\/jats:sub> purinoceptors sensitive to ATP and UDP, respectively, control the osteogenic commitment of BM-MSCs and, thus, bone growth and remodelling. Yet, this mechanism is impaired in post-menopausal (Pm)-derived BM-MSCs, mostly because NTPDase3 overexpression decreases the extracellular accumulation of nucleotides below the levels required to activate plasma membrane-bound P2 purinoceptors. This prompted us to investigate whether in vitro MS of BM-MSCs from Pm women could rehabilitate their osteogenic commitment and whether xenotransplantation of MS purinome-primed Pm cells promote repair of critical bone defects in an in vivo animal model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>BM-MSCs were harvested from the neck of femora of Pm women (70\u2009\u00b1\u20093 years old) undergoing total hip replacement. The cells grew, for 35 days, in an osteogenic-inducing medium either submitted (SS) or not (CTR) to MS (90 r.p.m. for 30\u00a0min) twice a week. Increases in alkaline phosphatase activity and in the amount of osteogenic transcription factors, osterix and osteopontin, denoted osteogenic cells differentiation, while bone nodules formation was ascertain by the alizarin red-staining assay. The luciferin-luciferase bioluminescence assay was used to quantify extracellular ATP. The kinetics of the extracellular ATP (100 \u00b5M) and UDP (100 \u00b5M) catabolism was assessed by HPLC. The density of P2Y<jats:sub>6<\/jats:sub> and P2X7 purinoceptors in the cells was assessed by immunofluorescence confocal microscopy. MS-stimulated BM-MSCs from Pm women were xenotransplanted into critical bone defects drilled in the great trochanter of femora of one-year female Wistar rats; bone repair was assessed by histological analysis 10 days after xenotransplantation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>MS-stimulated Pm BM-MSCs in culture (i) release 1.6-fold higher ATP amounts, (ii) overexpress P2X7 and P2Y<jats:sub>6<\/jats:sub> purinoceptors, (iii) exhibit higher alkaline phosphatase activity and overexpress the osteogenic transcription factors, osterix and osteopontin, and (iv) form larger bone nodules, than CTR cells. Selective blockage of P2X7 and P2Y<jats:sub>6<\/jats:sub> purinoceptors with A438079 (3 \u00b5M) and MRS 2578 (0.1 \u00b5M), respectively, prevented the osteogenic commitment of cultured Pm BM-MSCs. Xenotransplanted MS purinome-primed Pm BM-MSCs accelerated the repair of critical bone defects in the in vivo rat model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Data suggest that in vitro MS restores the purinergic cell-to-cell communication fostering the osteogenic differentiation and osteointegration of BM-MSCs from Pm women, a strategy that may be used in bone regeneration and repair tactics.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13287-024-03775-4","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T23:02:17Z","timestamp":1718665337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mechanical stimulation-induced purinome priming fosters osteogenic differentiation and osteointegration of mesenchymal stem cells from the bone marrow of post-menopausal women"],"prefix":"10.1186","volume":"15","author":[{"given":"Catarina","family":"Bessa-Andr\u00eas","sequence":"first","affiliation":[]},{"given":"Rui","family":"Pinto-Cardoso","sequence":"additional","affiliation":[]},{"given":"Karyna","family":"Tarasova","sequence":"additional","affiliation":[]},{"given":"Ana Lu\u00edsa","family":"Pereira-Gon\u00e7alves","sequence":"additional","affiliation":[]},{"given":"Joana Maria","family":"Gaio-Ferreira-Castro","sequence":"additional","affiliation":[]},{"given":"Liliana S.","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Maria Adelina","family":"Costa","sequence":"additional","affiliation":[]},{"given":"F\u00e1tima","family":"Ferreirinha","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Canadas-Sousa","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9","family":"Marinhas","sequence":"additional","affiliation":[]},{"given":"Rolando","family":"Freitas","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Lemos","sequence":"additional","affiliation":[]},{"given":"Ad\u00e9lio","family":"Vila\u00e7a","sequence":"additional","affiliation":[]},{"given":"Ant\u00f3nio","family":"Oliveira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6114-9189","authenticated-orcid":false,"given":"Paulo","family":"Correia-de-S\u00e1","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 Bernardo","family":"Noronha-Matos","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"issue":"12","key":"3775_CR1","doi-asserted-by":"publisher","first-page":"1726","DOI":"10.1007\/s00198-006-0172-4","volume":"17","author":"O Johnell","year":"2006","unstructured":"Johnell O, Kanis JA. 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All procedures were approved within the scope of the project \u201cBONE-PURI(NO)AGEING \u2013 Regeneration of aged human bone through purinome activation in mesenchymal stem cells \u2013 preclinical studies\u201d, followed by the project \u201cBONEREGENERA - New insights of the purinome in predicting bone healing by mesenchymal stromal cells in osteoporotic patients\u201d by the Ethics Committees of Centro Hospitalar de Vila Nova de Gaia \u2013 Espinho (registration n\u00ba 137\/2018-2, endorsed on January 10, 2019) and of Gabinete Coordenador de Investiga\u00e7\u00e3o \/ DEFI \u2013 Centro Hospitalar Universit\u00e1rio de Santo Ant\u00f3nio (CHUdSA, registration n\u00ba 2021-002(001-DEFI-001-CE, endorsed on September 01, 2021), and of Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (Medical School) of the University of Porto. The investigation conforms to the principles outlined in the Declaration of Helsinki. Animals care and experimental procedures were conducted in strict accordance with the recommendations of the European convention for the Protection of Vertebrate animals used for experimental and other Scientific purposes (ETS 123), Directive 2010\/63\/EU, and Portuguese rules (DL 113\/2013). All experimental protocols involving animals were approved by the competent national authority Dire\u00e7\u00e3o Geral de Alimenta\u00e7\u00e3o e Veterin\u00e1ria and by the ICBAS Animal Ethical Committee (No. 224\/2017); experimental design, data analysis, and reporting are in accordance to Curtis, Ashton, Moon, and Ahluwalia. []. All efforts were made to minimize animal suffering and to reduce the number of animals in compliance with the ARRIVE 2.0 guidelines Percie Du Sert et al. []. This exploratory study was not pre-registered.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and humans consent to participate"}},{"value":"The authors have declared that no conflict of interest exists.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"168"}}