Phase composition of calcium phosphate materials affects bone formation by modulating osteoclastogenesis

Human mesenchymal stromal cells (hMSCs) seeded on calcium phosphate (CaP) bioceramics are extensively explored in bone tissue engineering and have recently shown effective clinical outcomes. In previous pre-clinical studies, hMSCs-CaP-mediated bone formation was preceded by osteoclastogenesis at the implantation site. The current study evaluates to what extent phase composition of CaPs affects the osteoclast response and ultimately influence bone formation. To this end, four different CaP bioceramics were used, hydroxyapatite (HA), ß-tricalcium phosphate (ß-TCP) and two biphasic composites of HA/ß-TCP ratios of 60/40 and 20/80 respectively, for in vitro osteoclast differentiation and correlation with in vivo osteoclastogenesis and bone formation. All ceramics allowed osteoclast formation in vitro from mouse and human precursors, except for pure HA, which significantly impaired their maturation. Ectopic implantation alongside hMSCs in subcutis sites of nude mice revealed new bone formation at 8 weeks in all conditions with relative amounts for ß-TCP > biphasic CaPs > HA. Surprisingly, while hMSCs were essential for osteoinduction, their survival did not correlate with bone formation. By contrast, the degree of early osteoclastogenesis (2 weeks) seemed to define the extent of subsequent bone formation. Together, our findings suggest that the osteoclastic response could be used as a predictive marker in hMSC-CaP-based bone regeneration and strengthens the need to understand the underlying mechanisms for future biomaterial development.
This work was financially supported by the European Commission through the H2020 project ORTHOUNION (Grant Agreement: 733288) and by Campus France and the Austrian`s Agency for Education and Internationalisation through the PHC Amadeus 2018 program and the scientific and technological cooperation program “Amadée”. PH received a PhD fellowship from the Regional Council Pays de la Loire and the ORTHOUNION project. MAB received fundings from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Individual Fellowship, Grant Agreement No 708711. MPG and CC acknowledge PID2019-103892RB-I00/AEI/10.13039/501100011033 project from the Spanish Ministry of Science and Innovation and the SGR2017-1165 and the ICREA Academia Awards for Excellence in Research from the Generalitat de Catalunya.
Peer Reviewed
Objectius de Desenvolupament Sostenible::3 - Salut i Benestar
Postprint (published version)