Introduction
Osteoarthritis (OA) is a common degenerative and debilitating joint disease. It is a leading cause of disability and impaired quality of life in older adults ( Zhang et al., 2022 ) 1 . OA is considered an organ disease that affects the whole joint, including cartilage, subchondral bone, meniscus, synovium, and ligaments ( Hadzic & Beier, 2023 ). The pathology of OA includes cartilage loss, synovial hyperplasia, ligament fibrosis, osteophyte formation, subchondral bone remodeling and sclerosis, and increased cytokine production ( Aspden & Saunders, 2019 ). These pathological alterations cause joint pain, stiffness, and dysfunction. Although articular cartilage deterioration has traditionally been regarded as the primary cause of OA and numerous cartilage-preserving treatments have been developed, emerging evidence suggests subchondral bone maintenance and remodeling also play significant roles in OA pathophysiology ( Zhu et al., 2020 ). This process allows adaptation to cartilage degradation and helps maintain joint tissue homeostasis. Understanding how subchondral bone remodeling occurs in OA could provide valuable insights for the development of future therapies targeting this disease in its early stages. Subchondral bone plays a crucial role in the pathological process of OA and is an important source of pain. Many antiresorptive therapies used for osteoporosis target increased bone turnover in the subchondral region; therefore, these therapies have been explored as a means to target increased bone turnover in the subchondral region in OA, which occurs primarily in the early stages of the disease ( Eriksen et al., 2021 ). Zhu et al. (2019) demonstrated that osteoclasts derived from subchondral bone can induce sensory innervation and osteoarthritis pain; additionally, alendronate can inhibit osteoclast activity, alleviate aberrant subchondral bone remodeling, reduce innervation, and improve pain behavior in early-stage OA. Alendronate was shown to reduce subchondral bone turnover and bone loss and preserve articular cartilage ( Zhu et al., 2013 ; Khorasani et al., 2015 ). Alendronate was also found to inhibit vascular invasion into calcified cartilage in rats with OA and block osteoclast recruitment to subchondral bone and osteophytes ( Hayami et al., 2004 ). However, its mechanism of action has not been elucidated.

Large quantities of data, including bioinformatics datasets, have accumulated in the “big data” era ( Pal et al., 2020 ). High-throughput sequencing data collection has improved rapidly, leading to substantial advances in understanding of molecular mechanisms and the discovery of drug targets. Previous studies have demonstrated that changes in gene expression play important roles in OA diagnosis and development ( Tew et al., 2014 ; Coutinho de Almeida et al., 2019 ). Significant changes in the expression of genes related to enzymatic activity and the extracellular matrix (ECM) have been observed, including those responsible for producing proteinases such as ADAMTS1, ADAMTS5, and HTRA1. These studies also revealed specific genetic components previously implicated in OA progression, such as COL1A1, HAPLN1, CILP, IL6, WNT5A, IGFBP4, APOD, and DKK3. An integrated approach was used to analyze miRNA and mRNA sequencing data from OA cartilage, revealing the interactome of OA miRNAs and associated pathways. The study emphasized the impact of miRNAs on gene expression in cartilage and highlighted the challenges in functionally validating a network of genes targeted by multiple miRNAs. However, the pathological changes in OA differ between the lesioned and preserved sides in terms of cartilage and subchondral bone changes ( Omoumi et al., 2015 ). More research is needed to develop local therapies and precision medicine approaches for treating OA.

In this study, we compared the gene expression profiles of lesioned and preserved tibias in OA patients and identified associated genes, pathways, and immune cells. The results were validated using multiple tissue datasets and experiments.