Activation of Hedgehog Signaling Inhibits Osteoblast Differentiation of Human Mesenchymal Stem Cells.

Description

Mesenchymal stem cells within the bone are responsible for the generation of osteoblasts, chondrocytes and adipocytes. In rodents, Indian hedgehog (Ihh) has been shown to play a role in osteoblast differentiation. However, evidences for a direct function of Hedgehog (Hh) in human osteoblastic differentiation are missing. Using different models of human mesenchymal stem cells we show that Hh signaling decreases during osteoblast differentiation. This is associated with a decrease in Smoothened expression, a key partner that triggers Hh signaling, and in the number of cells displaying a primary cilium, an organelle necessary for Hh signaling. Remarkably, treatment of human mesenchymal stem cells with Shh or two molecules able to activate Hh signaling inhibits osteoblast differentiation. This inhibition is visualized through a decrease in mineralization and in the expression of osteoblastic genes. In particular, activation of Hh signaling induces a decrease in Runx-2 expression, a key transcriptional factor controlling the early stage of osteoblast differentiation. Consistently, the activation of Hh signaling during the first days of differentiation is sufficient to inhibit osteoblast differentiation, while differentiated osteoblasts are not affected by Hh signaling. In summary, we show here using various inducers of Hh signaling and mesenchymal stem cells of two different origins, that Hh signaling inhibits human osteoblast differentiation, in sharp contrast to what has been described in rodent cells. This species difference should be taken into account for screening for pro-osteogenic molecules. ______________________________________________________________________________ Author contributions: M.P.: Collection and assembly of data, Data analysis and interpretation, Manuscript writing; C.F.: Collection of data, Data analysis and interpretation; W.C.: Collection of data; N.R.: Data analysis and interpretation, Provision of study material; C.D.: Conception and design, Data analysis and interpretation, Financial support; P.P.: Conception and design, Collection and assembly of data, Data analysis and interpretation, Manuscript writing.

Abstract

International audience

Additional details