Osteoarthritis (OA) is the most common type of joint disease worldwide, characterized by joint pain, and limited mobility. The incidence of OA in middle-aged and elderly adults is approximately 40% and 80%, respectively [1]. The pain and loss of limb function caused by OA can promote aging. The etiology of OA is complex and multiple mechanisms are involved in the occurrence and development of the disease [2]. Unlike secondary OA, which has identifiable causes such as anatomical abnormalities, muscle imbalances, obesity, and excessive weight-bearing, the exact origin of primary OA remains elusive. Both types, however, share similar clinical manifestations, characterized by chronic pain, joint stiffness, swelling, decreased range of motion, and potential deformity [3]. In the early and middle stages of OA, poor alignment of lower limbs is common among patients which can be corrected surgically [4].

Tissues such as synovium, cartilage and joint fluid contribute to the occurrence and development of OA [3]. During OA, there are significant alterations in the local microenvironment, cellular and molecular levels. Some of such changes include persistent synovial inflammation, exudation, chondrocyte destruction, apoptosis, loss and stripping of articular surface cartilage, subchondral bone microfracture, subchondral bone exposure, subchondral bone sclerosis, peripheral hyperplasia, etc. [5] Currently, there are no effective treatments for OA, with advanced total joint replacement being the commonly used therapy. Cell therapy using cartilage-derived stem cells shows promising results, but concerns exist regarding its efficacy, safety, and potential for immune reactions [[6], [7], [8], [9]]. Studies suggest that extracellular vesicles (EVs) can alleviate metabolic imbalance within the extracellular matrix, potentially slowing OA progression owing to their anti-inflammatory and immunomodulatory properties [10]. Exosomes (Exos) are extracellular vesicles with a bilayer membrane structure, which are unique secretory vesicles in intercellular communication. Proteins, microRNAs (miRNAs) and other bioactive substances carried by Exos play an important role in immune response and antigen presentation [11]. Related studies have shown that Exos regulate the generation and progression of OA. Zhou et al. demonstrated that exosomal miRNA-126-3p derived from synovial fibroblasts constrained chondrocyte inflammation and cartilage degeneration in an OA rat model [12]. In addition, miR-221-3p was down-regulated in OA cartilage, which significantly affected the expression of matrix synthesis genes and chondrocyte proliferation and apoptosis [13]. Researchers are attempting to develop groundbreaking therapies for treating OA by engineering and customizing exosomes, tiny natural carriers released by cells [[14], [15], [16]]. These “programmed exosomes” can be equipped with specific biomolecules or modified drugs to target the disease directly, offering potential advantages over traditional treatments [17,18].

Despite ongoing research, there are no effective treatments for early- and middle-stage OA [19,20]. This highlights the need to explore the precise disease mechanisms and develop accurate diagnostic tools for early-stage OA. Given the significance of synovial tissue in OA progression, we developed a rat model to investigate changes in the microenvironment. The signaling molecules carried by tissue-specific exosomes and microscopic messengers released by cells were explored. Furthermore, the synovial tissue from different stages of OA (early and late) was examined to reveal the underlying pathological mechanisms. The findings of this study will pave the way for future development of diagnostic and personalized treatment strategies.