Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies

International Journal of Oral Science REVIEW ARTICLE www.nature.com/ijos OPEN Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies 1234567890();,: Yuangang Wu1, Jiao Li2, Yi Zeng1, Wenchen Pu2, Xiaoyu Mu2, Kaibo Sun1, Yong Peng2 ✉ and Bin Shen1 ✉ Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide. However, effective strategies for cartilage repair are lacking, and patients with advanced OA usually need joint replacement. Better comprehending OA pathogenesis may lead to transformative therapeutics. Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior. Specifically, exosome cargos, such as noncoding RNAs (ncRNAs) and proteins, play a crucial role in OA progression by regulating the proliferation, apoptosis, autophagy, and inflammatory response of joint cells, rendering them promising candidates for OA monitoring and treatment. This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA, suggesting new realms to improve OA management. International Journal of Oral Science (2022)14:40 ; https://doi.org/10.1038/s41368-022-00187-z INTRODUCTION Osteoarthritis (OA) is a chronic low-degree inflammatory disease mainly characterized by progressive degeneration of articular cartilage, thickening of the subchondral bone, synovial inflammation, meniscus and ligament degeneration, and osteophyte formation.1,2 The well-established risk factors for OA include age, sex, obesity, trauma, metabolism, and joint biomechanics.3–5 The chronic pain and dysfunction caused by OA affect over 250 million people worldwide,2 which severely reduces the life quality of individuals and represents a considerable socioeconomic burden.6 Currently, drug therapy serves as a fundamental strategy in the overall treatment of OA.7,8 Throughout the whole treatment process, most patients need short-term or long-term medication,7–9 including nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and drugs for intra-articular injection (e.g., hyaluronic acid and glucocorticoid). However, the current drug treatment of OA suggested by international guidelines is merely aimed at remission of disease symptoms, without substantial interruption of the destructive process or restoration of lesioned cartilage in OA.8–10 As for patients with end-stage OA, joint arthroplasty surgery represents a prevalent treatment modality, although sometimes the functional outcome can be unsatisfactory. Moreover, joint replacement requires more revision surgery in the case of complications such as infection and prosthetic fracture.11,12 Therefore, it is essential to clarify the molecular mechanisms underlying OA occurrence and progression to facilitate new therapies for future clinical needs. Joint cartilage tissue is in a complex microenvironment that contains not only chondrocytes but also a variety of nonchondrocyte types, such as adipocytes, synovial cells, mesenchymal stem cells (MSCs), endothelial cells, and immune cells.1,3,5 These cellular components can crosstalk with each other by secreting a variety of metabolic factors and inflammatory factors through paracrine, autocrine, and endocrine pathways and jointly maintain articular cartilage homeostasis, which is, however, heavily disrupted in OA. Accumulating evidence suggests that altered communication between chondrocytes and the surrounding tissues may directly or indirectly affect the progression of OA1,13 (Fig. 1). Upon exposure to risk factors that promote joint vulnerability, dysfunctional chondrocytes release excessive protease matrix-degrading enzymes, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), leading to the degradation of extracellular matrix (ECM).14 These degradative products are released into the synovial fluid, where they act as damage-associated molecular patterns (DAMPs) to trigger the inflammatory response of adjacent synovial cells (e.g., synovial fibroblasts, macrophages, and mast cells). Subsequently, OA-related immune components, including proinflammatory cytokines (e.g., interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factoralpha (TNF-α)), growth factors (e.g., transforming growth factor-beta, (TGF-β)), chemokines and adipokines, are aggregated and further promote the activity of MMPs and ADAMTSs, initiating vicious feedback of local tissue damage and low-grade inflammation.14,15 Therefore, exploring how cells communicate within cartilage microenvironments may help to unveil the pathogenesis of OA and explore new strategies for future treatment of OA. Recently, exosomes have emerged as a new medium involved in cell–cell communication.16,17 A variety of cellular components, in particular noncoding RNAs (ncRNAs), can be preferentially 1 Orthopedic Research Institute, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China and 2Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China Correspondence: Yong Peng () or Bin Shen () These authors contributed equally: Yuangang Wu, Jiao Li Received: 19 April 2022 Revised: 2 June 2022 Accepted: 14 June 2022 Exosomes rewire the cartilage microenvironment in osteoarthritis: from. . . Wu et al. 2 a b Risk factors for OA Inflammation and cartilage loss • Age MMPs, ADAMTS • Sex • Obesity ECM products • Trauma • Genetic DAMPs Cytokines: IL-Lβ, IL-6, TNF-α Chemokines: CCL2, CCL5 Growth factor: TGF-β Complement: C3, C5a, TLR2, TLR4 • Metabolism • Joint biomechanics Femur Adipokines Osteophyte Articular cartilage c Fibraus layer Subchondral bone remodeling Articular Synovial layer Subchondral bone cyst Fibula Tibia Synovial fibroblast Normal chondrocyte Extracellular matrix Tidemark duplication Macrophage Hypertrophic chondrocyte Bone marrow stem cell Subchondral bone sclerosis Mast cell Senscent chondrocyte Osteoblast Nerve invasion Infrapatellar fat pad Apoptotic chondrocyte Osteoclast Vascular invasion Fig. 1 The inflammatory network and pathobiology in OA. a Risk factors for OA. Evidence suggests that specific systemic risk factors (e.g., age, obesity, and sex) and mechanical factors (e.g., trauma and joint biomechanics) are capable of causing cartilage damage in OA. b Inflammatory network in OA. The degradation products of cartilage and extracellular matrix (ECM) components are released into the joint cavity as damageassociated molecular patterns (DAMPs), which ultimat (...truncated)