Study of the biological relevance of Wnt/β-catenin signaling pathway and β-adrenergic regulation in osteoblastic differentiation of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) can invade the bone site, proliferate and differentiate into cartilage and bone. Therefore, they serve as an important target for developing modalities to enhance local and systemic bone formation. It has been demonstrated that the Wnt/β-catenin signaling pathway plays a key role in the movement of MSCs toward osteoblast lineage. β-Catenin, an indispensable mediator of canonical Wnt signaling, is a transcriptional factor regulating the mesenchymal precursor's differentiation to mature osteoblasts. On the other hand, the β-adrenergic nervous system negatively impacts the osteogenic differentiation of MSCs. β-Adrenergic receptors (β-AR) are the dominant synergistic receptors on MSCs. It is established that catecholamines activate β-adrenergic receptors and inhibit osteoblastogenesis through an unknown molecular mechanism. This study evaluated the β-adrenergic system mediates inhibition of osteoblastogenesis through the inhibition of the Wnt/β-catenin signaling pathway. Hence, we have treated MSCs with a β-adrenergic agonist (Isoproterenol) and a β-adrenergic antagonist (propranolol). Next, on days 7 and 14 post-treatment, we have examined mineralization, osteogenic markers and the expression of genes related to Wnt signaling. Our findings suggested that isoproterenol (β-adrenergic agonist) inhibits the differentiation of mesenchymal stem cells to osteoblasts via stimulation of β2-adrenergic receptor and the subsequent inhibition of Wnt β-catenin signaling by lowering the expression of β-catenin. Nevertheless, the SOST expression did not exhibit a meaningful pattern to support that Isoproterenol inhibits the Wnt signaling pathway by increasing sclerostin expression.