The Effects of Neurotransmitters in Chondrocytes and Cartilage Biology

Neurotransmitters are key factors for cell communication within the central and peripheral nervous systems. Recent evidence indicates that they also regulate the function of non-neuronal tissues, including cartilage, as chondrocytes express neurotransmitter receptors, transporters, and other signaling molecules, enabling them to respond to neurochemical cues affecting homeostasis and disease. This review synthesizes the current literature on the roles of major neurotransmitters in chondrocytes and cartilage biology, focusing on norepinephrine, glutamate, γ-aminobutyric acid (GABA), acetylcholine, and serotonin. Specifically, we conducted an extensive literature review within major databases such as PubMed and Scopus, which led to 2748 papers being screened based on various inclusion/exclusion criteria. A total of 42 relevant manuscripts were further selected and are presented to describe the role of neurotransmitters in chondrocytes/cartilage. The data demonstrate that neurotransmitter signaling regulates diverse aspects of chondrocyte biology, including proliferation, differentiation, endochondral ossification, mechanotransduction, extracellular matrix remodeling, inflammation, apoptosis, autophagy, and osteoarthritis (OA). Norepinephrine is the most extensively studied neurotransmitter and exhibits context-dependent effects on cartilage development, OA progression, and repair through adrenergic receptor signaling and neuroendocrine pathways. Glutamatergic signaling, particularly through N-methyl-D-aspartate (NMDA) receptors, is implicated in mechanotransduction, inflammatory activation, circadian regulation, and OA-associated phenotypic changes, whereas GABAergic signaling primarily regulates growth plate maturation and chondrogenesis. Finally, acetylcholine signaling appears to promote chondrocyte survival and anti-inflammatory responses, while serotonin is linked to altered calcium signaling, inflammatory mediator production, and cartilage catabolism. The biological effects of these neurotransmitters are highly dependent on receptor subtype, disease stage, inflammatory status, and mechanical environment, highlighting the complexity of neuro-cartilage communication. Although significant knowledge gaps remain regarding receptor-specific mechanisms and translational significance, current data support neurotransmitter signaling as an important regulator of cartilage and a promising avenue for the development of novel therapeutic strategies for OA.