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Osteoblasts (OSTs) are derived from mesenchymal stem cells (MSCs) and coexist in close proximity with MSCs in bone during development and remodelling. Interactions between these two cell types remain obscure. Through a well-defined co-culture model, the present work demonstrated that OSTs regulate MSCs through the WNT and cadherin pathways. The regulation mechanism depends on the cell-cell contact mode (indirect or direct) between the two cell types. When physically separated (indirect contact), OSTs express WNTs and stimulate the osteogenic differentiation of MSCs through the activation of the WNT pathway and suppression of the cadherin pathway. This mechanism is evidenced by: (a) the elevation of cytoplasmic and nuclear unphosphorylated beta-catenin protein levels; (b) the suppression of beta-catenin degradation; (c) the increase in WNT-related transcription factor TCF1/LEF1; and (d) the loss of major bone-related cadherins (N-CAD and CAD11). Addition of DKK1 antagonizes the WNT pathway and diminishes the stimulatory effect of OSTs on MSCs. When in direct cell-cell contact, OSTs still secrete WNTs, whose binding still stabilizes the beta-catenin in MSCs. However, direct cell-cell contact induces the upregulation of cadherin pathway in MSCs, which suppresses the WNT pathway by containing cytoplasmic beta-catenin protein at a low level; consequently, the stimulatory effect of OSTs is negated. Regulation of cytoplasmic beta-catenin protein levels through concerted action or crosstalk between the WNT and cadherin pathways is the key to the signalling transduction in these cellular communication networks.

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