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Significance Bone formation occurs through two distinct pathways, namely, endochondral ossification (EO) and intramembranous ossification (IMO). While significant effort has gone into understanding the role of various soluble signals in EO and IMO, the impact of the bone inorganic interface in triggering these ossification pathways has remained unexplored. Herein, we report the discovery that the bone-like mineral phase promotes formation of bone by mesenchymal stem/stromal cells (MSCs) exclusively via IMO even in the presence of soluble signals that promote the EO paradigm. Furthermore, we provide mechanistic insights into our observations and illustrate a previously unidentified role for extracellular calcium-sensing receptor (CaSR) in dictating the choice of ossification pathway in MSCs. These findings have significant implications for developing new strategies for bone repair and understanding bone homeostasis.

Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R