Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via ?2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation.

ABSTRACT: Bone marrow-derived mesenchymal stem cells (BMSCs) represent an alternative to chondrocytes to support cartilage regeneration in osteoarthritis (OA). The sympathetic neurotransmitter norepinephrine (NE) has been shown to inhibit their chondrogenic potential; however, their proliferation capacity under NE influence has not been studied yet. Therefore, we used BMSCs obtained from trauma and OA donors and compared the expression of adrenergic receptors (AR). Then, BMSCs from both donor groups were treated with NE, as well as with combinations of NE and ?1-, ?2- or ?1/2-AR antagonists (doxazosin, yohimbine or propranolol). Activation of AR-coupled signaling was investigated by analyzing ERK1/2 and protein kinase A (PKA) phosphorylation. A similar but not identical subset of ARs was expressed in trauma (?2B-, ?2C- and ?2-AR) and OA BMSCs (?2A-, ?2B-, and ?2-AR). NE in high concentrations inhibited the proliferation of both trauma and OA BMCSs significantly. NE in low concentrations did not influence proliferation. ERK1/2 as well as PKA were activated after NE treatment in both BMSC types. These effects were abolished only by propranolol. Our results demonstrate that NE inhibits the proliferation and accordingly lowers the regenerative capacity of human BMSCs likely via ?2-AR-mediated ERK1/2 and PKA phosphorylation. Therefore, targeting ?2-AR-signaling might provide novel OA therapeutic options.

SUBMITTER: Hedderich J 

PROVIDER: S-EPMC7312191 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature