A growing understanding of purinergic signaling is reshaping how scientists view osteoarthritis (OA), revealing an intricate communication network that influences joint inflammation, cartilage degeneration, bone remodeling, and chronic pain. A new review article highlights how disruptions in this signaling system may play a central role in disease progression while identifying promising opportunities for more targeted therapies that could slow or modify the course of OA rather than simply relieve symptoms.
Osteoarthritis is the most common form of arthritis and a leading cause of pain and disability worldwide. Once regarded primarily as a consequence of mechanical wear and tear, it is now understood to involve complex biological processes that affect the entire joint. The review explains that purinergic receptors, which respond to molecules released by damaged or stressed cells, help regulate normal joint function but become dysregulated during osteoarthritis, driving inflammation and tissue damage.
The article describes two major groups of receptors with contrasting roles. P2 receptors respond to extracellular nucleotides such as ATP and are associated with inflammatory signaling, cartilage breakdown, and pain when excessively activated. In contrast, P1 receptors, which respond to adenosine, generally support protective processes that help maintain cartilage integrity, reduce inflammation, and promote tissue repair. The balance between these signaling pathways appears to be essential for preserving healthy joint function.
The review outlines how specific receptor subtypes influence different aspects of osteoarthritis. Some contribute to inflammatory pathways that damage cartilage and alter the underlying bone, while others are closely linked to the development of persistent pain. At the same time, protective receptors may enhance autophagy, improve mitochondrial function, reduce oxidative stress, and help preserve the extracellular matrix that provides cartilage with its strength and resilience.
The authors also discuss the therapeutic potential of selectively targeting these signaling pathways. Strategies aimed at blocking harmful P2 receptor activity while enhancing beneficial P1 receptor signaling could provide a more comprehensive approach to managing osteoarthritis by addressing both structural damage and pain. Although several candidate compounds are being explored, further development is needed to improve receptor selectivity, minimize unwanted effects, and optimize delivery to affected joints.
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Hongliang Li, Tianqi Wang, Zi Wang, Jincen Hou, Zhong Li, Jiyuan Yan, Purinergic signaling in osteoarthritis: Mechanistic insights into pathogenesis and therapeutic targeting, Genes & Diseases, Volume 13, Issue 5, 2026, 102002, https://doi.org/10.1016/j.gendis.2025.102002

Funding
Sichuan Science and Technology Program (China) 2022YFS0628
Doctoral Research Initiation Fund of Affiliated Hospital of Southwest Medical University