Osteocyte differentiation is regulated by extracellular matrix stiffness and intercellular separation
Mullen, Conleth A.
Haugh, Matthew G.
Schaffler, M. B.
Majeska, R. J.
McNamara, Laoise M.
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Mullen, C. A., Haugh, M. G., Schaffler, M. B., Majeska, R. J., & McNamara, L. M. (2013). Osteocyte differentiation is regulated by extracellular matrix stiffness and intercellular separation. Journal of the Mechanical Behavior of Biomedical Materials, 28, 183-194. doi: http://dx.doi.org/10.1016/j.jmbbm.2013.06.013
Osteocytes are terminally differentiated bone cells, derived from osteoblasts, which are vital for regulation of bone formation and resorption. ECM stiffness and cell seeding density have been shown to regulate osteoblast differentiation, but the precise cues that initiate osteoblast-osteocyte differentiation are not yet understood. In this study we cultured MC3T3-E1 cells on (A) substrates of different chemical composition and stiffness, as well as, (B) substrates of identical chemical composition but different stiffness. The effect of cell separation was investigated by seeding cells at different densities on each substrate. Cells were evaluated for morphology, alkaline phosphatase (ALP), matrix mineralisation, osteoblast specific genes (Type 1 collagen, Osteoblast specific factor (OSF-2)), and osteocyte specific proteins (dentin matrix protein 1 (DMP1), sclerostin (Sost)). We found that osteocyte differentiation (confirmed by dendritic morphology, mineralisation, reduced ALP, Col type 1 and OSF-2 and increased DMP1 and Sost expression) was significantly increased on soft collagen based substrates, at low seeding densities compared to cells on stiffer substrates or those plated at high seeding density. We propose that the physical nature of the ECM and the necessity for cells to establish a communication network contribute substantially to a concerted shift toward an osteocyte-like phenotype by osteoblasts in vitro.
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