Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-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 α1-, α2- or β1/2-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 (α2B-, α2C- and β2-AR) and OA BMSCs (α2A-, α2B-, and β2-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 β2-AR-mediated ERK1/2 and PKA phosphorylation. Therefore, targeting β2-AR-signaling might provide novel OA therapeutic options.

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

“…In contrast, b 2 -AR stimulating effects of SH1293 (i.e., terbutaline) have previously been demonstrated to promote chondroclastic activity by inducing RANKL (45,82). At high, but not low concentrations, norepinephrine can inhibit chondrogenesis in BMSCs via ERK1/2 and PKA mediation, effects that are blocked by the b 2 -AR blocker, propranolol (83). Our data indicates that treatment with SH1293 delayed and suppressed articular cartilage resorption in the distal tibia in arthritic rats, findings that support direct inhibitory effects of terbutaline on chondrocyte proliferation.…”

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…Akin to iSCs, MSCs also have multipotent stem cell activity. MSCs reside in multiple organs, including bone marrow, umbilical cord, amnion, and brain [ 90 , 91 , 92 , 93 ]. Although it remains unclear whether brain pericytes are identical to brain MSCs [ 94 ], it was reported that the traits of MSCs differ among organs [ 95 ].…”

Sympathetic influences on articular cartilage regeneration capacity and osteoarthritis manifestation

“…Furthermore, autocrine and paracrine effects of sASCs can be excluded because TH was neither detected in monolayer nor in chondrogenic sASCs cultures. This is in agreement with previous findings in OA chondrocytes (Speichert et al 2019) or BMSC derived from trauma or OA patients that did not express TH (Jenei-Lanzl et al 2014;Hedderich et al 2020). Since joint resident MSC and chondrocytes express AR, an interaction between these cells with neurotransmitters including NE was proposed, which is also supported by other studies (Takarada et al 2009;Mitchell et al 2011).…”

“…This study, demonstrated that the treatment with NE was not toxic in any of the tested concentrations and did not influence cell proliferation, indicating that NE in the knee-joint might not influence the proliferation or viability of sASCs. This is in line with another study showing that NE did not affect the viability of human OA chondrocytes (Speichert et al 2019) Interestingly, the proliferation of both OA and trauma BMSC was inhibited dose-dependently by NE without affecting cell viability (Hedderich et al 2020). Treatment with the highest concentration of 10 −6 M NE reduced the proliferation of OA BMSC significantly through the activity of β2-AR signalling pathway.…”

“…In the present study, the expression of several AR subtypes in sASCs was confirmed, indicating that sASCs are target cells of the SNS. AR gene expression in ASCs derived from OA synovial tissue was not demonstrated before, while ARs have been detected in OA BMSC (Hedderich et al 2020). In general, studies regarding AR expression in ASCs are sparse.…”