Norepinephrine modulates osteoarthritic chondrocyte metabolism and inflammatory responses

Abstract

Objective: Norepinephrine (NE) was measured in synovial fluid of trauma patients and sympathetic nerve fibers were detected in healthy and osteoarthritic (OA) joint tissues indicating that cartilage pathophysiology might be influenced by sympathetic neurotransmitters. The aim of this study was to elucidate the mostly unknown role of NE in OA chondrocyte metabolism and inflammatory responses.

Methods: Articular cartilage was received after total knee replacement surgery from OA patients. Expression of adrenergic receptors (AR) and tyrosine hydroxylase (TH) was tested with end point polymerase chain reaction (PCR) and immunohistochemistry. 3-dimensional (3D) cell cultures were employed to analyze effects of NE on chondrocyte cell metabolism and the expression of interleukins (ILs), matrix metalloproteases (MMPs), tissue inhibitor of metalloproteases (TIMPs), glycosaminoglycan (GAG) and collagen II under non- and inflammatory conditions. Chondrocyte monolayer cultures were used to specify AR subtypes, to analyze cell cycle distribution and to determine catecholamines in cell culture supernatants.

Results: AR subtypes and TH were detected in chondrocytes, whereas NE was not released in measurable amounts. 10(-6) M NE reversed IL-1β induced changes in IL-8, MMP-13, GAG and collagen II expression/production indicating for β-AR signaling. Additionally, NE caused cell cycle slow down and decreased proliferation via β-AR signaling. 10(-8) M NE increased the number of proliferating cells and induced apoptosis via α1-AR signaling.

Conclusions: NE affects chondrocytes from OA cartilage regarding inflammatory response and its cell metabolism in a dose dependent manner. The sympathetic nervous system (SNS) may have a dual function in OA pathology with preserving a stable chondrocyte phenotype via β-AR signaling and OA pathogenesis accelerating effects via α-AR signaling.

Keywords: Articular chondrocytes; IL-1β; Norepinephrine; Osteoarthritis; Sympathetic nervous system.