In mammals, collagen is the most abundant protein and one of the most abundant components of the extracellular matrix (ECM), accounting for more than one-third of the body’s protein tissue weight [1,2]. To date, approximately 28 types of collagen have been identified [3]. Collagen has a complex supramolecular structure, exists in highly diverse forms in different tissues, and has a range of biological functions [4]. In addition, collagen, as the basic structural component of connective tissue, plays a crucial role in maintaining its structural and biological integrity.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are the most prevalent painful and disabling diseases worldwide [5]. OA is a chronic degenerative disease, and the main causes of OA are senescence, trauma, mechanical loading, and obesity [6]. RA is an inflammatory autoimmune disease in which the patient’s body’s immune tolerance balance is disrupted, producing large amounts of pro-inflammatory cytokines, matrix-degrading enzymes, and autoantibodies, ultimately leading to synovial inflammation and joint damage [7,8]. Destruction of articular cartilage represents a common pathological feature of OA and RA. In articular cartilage, numerous collagen subtypes have been identified; the major and most abundant collagens are type I, II, IX, and XI collagens, and the minor and less abundant collagens are type III, IV, V, VI, X, XII, XIV, XVI, XXII, and XXVII collagens [9,10]. These collagens have a significant role in maintaining the mechanical properties of articular cartilage and the stability of the ECM. During the pathophysiology of arthritis, the cartilage collagen network undergoes irreversible degradation, and the fragments formed by its degradation can be used as biomarkers of ECM degradation and disease progression [10,11]. It can overcome some limitations of current disease assessment methods and has been extensively studied [11]. Articular cartilage is a highly specialized connective tissue that lacks blood vessels, lymphatics, and nerves and is characterized by its limited capacity to heal after injury [12,13]. Currently, there is no cure for OA and RA. Existing treatments aim to reduce pain and symptoms, as well as improve joint functional capacity [14]. Therefore, the proper healing of articular cartilage injury has been one of the significant medical issues that needs to be addressed. In addition, collagen has the potential as a biomaterial for bone tissue engineering due to its abundance, biocompatibility, high porosity, ease of binding to other materials, ease of processing, hydrophilicity, low antigenicity, and restorability in vivo [2].

Articular cartilage is primarily a tissue without blood arteries, nerves, or lymphatic vessels that absorbs and buffers stress [12]. Typically, it is composed of a sparse distribution of chondrocytes and a dense extracellular matrix. Chondrocytes are the only cell type in cartilage tissue and are responsible for the synthesis and maintenance of the basic structure of articular cartilage ECM [91]. Cartilage ECM is mainly composed of type Ⅱ collagen (Col Ⅱ), proteoglycan (PG), and water. The ECM plays an important role in the morphogenesis and cellular metabolism of new tissues, endowing them with mechanical and biochemical properties [18]. Type II collagen accounts for 90% to 95% of collagens in the ECM and is interwoven with proteoglycan aggregates to form fibrils and fibers. Type I, IV, V, VI, IX, and XI collagens, and other minor collagens, are also present and contribute to the formation and stabilization of the type II collagen fiber network [54]. Proteoglycans are also the major macromolecules in the ECM that occupy the interfibrillar space of cartilage ECM and provide permeability properties to cartilage [54]. Under normal physiological conditions, cartilage ECM synthesis and metabolism are in dynamic balance, which is important for maintaining the integrity and functionality of cartilage tissue [92].

The articular cartilage zone can be divided into four levels of organization from the articular surface to the bone marrow cavity based on the arrangement of cells and matrix fibrils. These levels include the surface layer, the middle or transition layer, the deep layer, and the calcified cartilage layer [93,94,95]. The surface layer accounts for 10–20% of the total cartilage width and encloses elongated chondrocytes [54,96,97]. They realize the secretion of type II, IX, and XI collagen fibers, which are found parallel to the surface [96]. The following zone, termed the middle or transition layer, accounts for 40–60% of the cartilage volume and consists of rounded chondrocytes surrounded by collagen fibers with a more random, sloped organization [54,96,97]. The deep layer accounts for 30–40% of the cartilage volume, and chondrocytes are typically aligned in columns parallel to the collagen fibers. The thinnest layer is the calcified cartilage layer, which occupies 2–3% of the width. It contains a small number of hypertrophic chondrocytes and is separated from the rest of the area by calcified lines [54,96,97].

In addition, depending on the proximity to chondrocytes and the organization of collagen fibers, the cartilage matrix can be divided into different zones: the pericellular region, the territorial region, and the interterritorial region [54]. The pericellular matrix is a narrow tissue region surrounding the chondrocytes, and it contains mainly proteoglycans, as well as glycoproteins and other non-collagenous proteins [98]. The PCM serves as a transducer of both biomechanical and biochemical signals for the chondrocyte [94]. The territorial matrix surrounds the pericellular matrix, which is composed mainly of fine collagen fibers that form a basket-like network around the cells. This region is thicker than the pericellular matrix and may contribute to the resilience of the articular cartilage structure and its ability to withstand heavy loads. The interterritorial region is the largest of the three matrix regions, and it provides the greatest contribution to the biomechanical properties of the articular cartilage [9,54].

However, in disease states, the synthesis and metabolism of cartilage’s ECM is disrupted, and irreversible degradation occurs when degradation exceeds synthesis. With the development of injury, cartilage changes toward hypertrophy and fibrosis. Hypertrophic chondrocytes tend to express type X collagen, and fibrosis is manifested by the deposition of type I and III collagens [14]. In injured articular cartilage, the expression of proteases, including MMP, ADAMTs, and cathepsin, has been found to be elevated. In addition to this, the damaged cartilage also showed articular cartilage fractures, calcified layer hypertrophy, and vascular invasion [96].

Rheumatic and joint diseases, as exemplified by OA and RA, are among the most common and widespread painful and disabling pathologies across the globe [5]. Cartilage plays an active role in OA and RA by acting as a signaling scaffold harboring bioactive matrix components and soluble factors that interact with embedded chondrocytes and are released upon cartilage degradation. Cartilage damage is a crucial feature of RA and OA, and common mechanisms have been shown to play a role in OA and RA cartilage injury. The enzymes that ultimately mediate cartilage ECM degradation show substantial overlap between OA and RA, including many MMPs, metalloproteinases, and cathepsins [99,100]. Among the MMPs, MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, and MMP-14 have attracted special interest [99,100]. Among them, the functional importance of MMP-13 in cartilage destruction has been demonstrated. MMP-13 is absent in normal adult cartilage and is specifically expressed in cartilage of OA and RA patients [101]. It is the major collagenase in cartilage and has the highest activity on type II collagen. In addition to MMP-13, metalloproteinases (A disintegrins and metalloproteinases with thrombospondin motif protein family, ADAMTS), ADAMTS-4, and ADAMTS-5 are most closely associated with cartilage damage, are involved in articular cartilage degradation, and are potential therapeutic targets for arthritis treatment [102,103]. In addition, it is essential to study the events that trigger cartilage damage and the differences between physiological cartilage remodeling and unbalanced cartilage destruction in OA and RA.

OA is an age-related chronic degenerative disease that results mainly from senescence, trauma, and mechanical stress but is also influenced by obesity, inflammation, genetics, and metabolism [6]. The main features of OA are progressive degeneration of the cartilage matrix, bone redundancy formation, subchondral osteosclerosis, and synovial inflammation [96]. In OA, different stress stimuli activate chondrocytes, causing a loss of phenotypic stability, cartilage ECM degradation, and low-level inflammation.

Senescence has been recognized as the most prominent risk factor for OA. With aging, many molecular pathways become unregulated, disrupting the dynamic balance of the ECM in cartilage and destroying cartilage structures. Senescence is characterized by permanent cell cycle arrest and the release of harmful pro-inflammatory molecules into the surrounding microenvironment, a feature known as the senescence-associated secretory phenotype (SASP) [104]. Another feature of senescence is mitochondrial dysfunction, which can increase cellular ROS levels to cause oxidative stress [105]. Oxidative stress can cause an imbalance of catabolic and anabolic signals in OA cartilage. Many SASP and some elevated ROS levels can be detected in articular cartilage and synovial tissue in OA, which can lead to the loss of articular cartilage type II collagen and cartilage destruction. In addition, the structure of collagen fibers changes with aging, affecting the collagen network’s stability and integrity [106].

Joint injury is a significant risk factor for osteoarthritis. In younger patients and highly active individuals, articular cartilage may be damaged by abnormal mechanical loading or trauma [107]. Joint injury may result in the release of inflammatory cytokines that induce chondrocytes to produce MMPs, aggregates, and other enzymes, leading to increased cartilage matrix degradation [108]. MMP-13 is the primary type II collagen-degrading collagenase involved in the degeneration of articular cartilage structures.

Obesity is another significant risk factor for knee OA. Obesity not only leads to increased joint loading but also enhances adipokine production in adipose tissue, which can lead to inflammatory or autoimmune diseases. Adipokines can also act as SASPs involved in the cellular senescence of chondrocytes [105,109]. Adipokines mainly include adiponectin, leptin, chemokines, and resistin, as well as tumor necrosis factor (TNF-α) and inflammatory cytokines (IL-6). Lipocalin is considered to be one of the adipokines associated with the pathogenesis of OA and is a potential catabolic mediator in OA. It increases NO and MMP-1, MMP-3, and MMP-13 levels in chondrocytes mainly through the AMPKJNK pathway in vitro, as well as causes an increase in type II collagen neoepitopes cleaved by collagenase in OA. This indicates the involvement of lipocalin in OA cartilage matrix degradation [110]. Moreover, lipocalin stimulates the increased expression of aggrecan, Runx2, and type X collagen, contributing to the change in chondrocytes towards the hypertrophic phase [111]. Leptin is the most widely studied adipokine, and it has been found to be highly expressed in human OA. Leptin has been shown to upregulate MMP-1 and MMP-3 production in OA cartilage and positively correlate with MMP-1 and MMP-3 in the synovial fluid of OA patients [112]. Treatment of chondrocytes with leptin promotes proliferation, differentiation, type X collagen production, and cytoskeletal remodeling via the RhoA/RhoA kinase (ROCK) pathway [113].

There is growing evidence that inflammatory pathways are associated with OA, but whether inflammation is a key trigger or a secondary phenomenon remains controversial. Inflammation is a chronic, aseptic, low-grade inflammatory state that triggers a cascade response of chondrocytes to a phenotypic shift toward hypertrophy, cartilage destruction, and bone remodeling by affecting chondrocyte metabolism. It also involves metabolic pathways as well as activation of the innate immune system [100,114].

RA is considered to be a systemic polyarticular chronic inflammatory autoimmune joint disease caused by complex interactions between genetic and environmental factors. This results in a disruption of the body’s immune tolerance balance and the production of large amounts of pro-inflammatory cytokines, matrix-degrading enzymes, and autoantibodies, ultimately leading to synovial inflammation and joint damage [8]. Chronic inflammation and cellular activation characterize the pathophysiology of RA, and fibroblast-like synoviocytes (FLS) are the key mediators of progressive stromal destruction [115]. In RA, synovial cells are activated to transform into a disease-specific, tumor-like, permanently imprinted phenotype [8,116]. Tumor-like transformation is a critical distinction between RA and OA, an essential feature of rheumatoid cartilage injury. The synovial immunopathology of RA has been well documented in that during the course of the disease, inflamed synovial cells, particularly FLS, attack the cartilage and cause its progressive destruction [115,116].

Articular cartilage destruction in RA is closely associated with the inflammatory environment. The synovial lining layer is the primary site of inflammation in RA. The resident cells here are FLS and synovial tissue macrophages (STM), which translate into overproduction of enzymes that degrade cartilage and bone, as well as cytokines that promote immune cell infiltration [117]. In patients with RA, the balance between pro-inflammatory and anti-inflammatory cytokines is disrupted and inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, are released in large amounts [118]. The inflammatory environment causes chondrocytes to secrete large amounts of matrix-degrading enzymes. The ECM synthesis metabolism balance is disturbed, leading to the degradation of the cartilage ECM from within, which is the central link leading to the destruction of cartilage structure [119].

Autoantibodies are an extensively studied topic in RA, and many autoantibodies have been identified as markers of RA. A variety of well-characterized autoantigens are present in patients with RA, such as guanosine proteins and peptides, components of articular cartilage (type II collagen), circulating serum proteins, enzymes, and other target proteins [120]. Autoantibodies against these autoantigens, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), and increased expression of anti-collagen type II antibodies are present. In different mouse models, autoantibodies have been shown to induce arthritis. Collagen antibody-induced arthritis (CAIA) is induced by the injection of a mixture of anti-collagen type II antibodies, leading to inflammation and bone and cartilage erosion of the joint [121]. RF and ACPA are the two most representative autoantibodies in the diagnosis of RA, which help in the treatment and prognosis of RA [122].