Modeling the chondrocyte-derived osteoblasts formation process reveals its molecular signature and regulation network
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Raquel Ruiz-Hernández Laurie Gay Veronica Moncho Amor Pablo Martín Jhonatan A Vergara-Arce Stefania Di Blasio Thomas Snoeks Unai Cossío Ander Matheu Maria M Caffarel Daniela Gerovska Marcos J Araúzo-Bravo Amaia Vilas Felipe Prosper Sergio Moya Daniel Alonso-Alconada Ana Alonso-Varona Gretel Nusspaumer Javier Lopez-Rios Karine Rizzoti Robin Lovell-Badge Dominique Bonnet Ilaria Malanchi Ander Abarrategi

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Abstract

Endochondral ossification is a physiological process involving a sequential formation of cartilage and bone tissues. Classically, cartilage and bone formation have been considered independent processes at cellular level. However, the recently described multiple cell differentiation dynamics suggest that some bone cells are indeed the progeny of cartilage cells, or chondrocyte-derived osteoblasts. We hypothesized that the cartilage-to-bone phenotype transition is triggered by specific molecular events. First, the process was assessed in mouse bone tissue, and then, it was mimicked using in vivo cell implantation and in vitro serial differentiation protocols. Data indicates that cartilage cells transition to bone cell phenotype during postnatal physiological bone formation. This process can be reproduced using cartilage precursor cells coupled to specific implantation procedures or differentiation protocols. Gene expression profiling reveals that NOTCH, BMP and MAPK signaling pathways are relevant at the phenotype-switch, while the transcription factors Mesp1, Alx1, Grhl3 and Hmx3 are the feasible driver genes for chondrocyte-derived osteoblasts formation. Altogether, this report shows that endochondral ossification can be modeled using primary cell cultures and data indicate that this process is regulated by specific molecular events, previously described at skeleton morphogenesis during embryo development, and from now on also linkable to postnatal bone development and regeneration processes.