Abstract

Background: Connective tissue disorders such as rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus are characterized by chronic inflammation and collagen degradation, which contribute to tissue damage and disease progression. Specific Background: Collagen degradation biomarkers, including matrix metalloproteinases (MMP-1, MMP-9), tissue inhibitors of metalloproteinases (TIMP-1), and inflammatory markers (CRP, TNF-α), reflect the extent of tissue remodeling and inflammation. However, limited studies comprehensively evaluate their diagnostic and prognostic value in these disorders. Knowledge Gap: There is insufficient evidence comparing the levels of these biomarkers between patients with connective tissue disorders and healthy individuals, particularly regarding their role in disease monitoring and progression. Aims: This study aims to assess and compare collagen degradation biomarkers (MMP-1, MMP-9, TIMP-1, CTX, CRP, TNF-α) between patients with connective tissue disorders and healthy controls to explore their diagnostic and prognostic significance. Results: Patients exhibited significantly elevated levels of MMP-1, MMP-9, TIMP-1, CTX, CRP, and TNF-α compared to healthy controls (p < 0.05), suggesting increased collagen turnover and chronic inflammation. BMI was also significantly higher in patients (p = 0.003). Novelty: This study provides comprehensive comparative data on multiple biomarkers, highlighting the simultaneous elevation of collagen degradation and inflammatory markers as potential indicators for disease severity. Implications: These findings suggest that assessing collagen degradation biomarkers can enhance early diagnosis, monitor disease progression, and guide therapeutic strategies for connective tissue disorders.

Highlights:

1. Collagen biomarkers indicate tissue damage in connective tissue disorders.
2. Compare collagen biomarkers in patients and healthy controls for diagnostic value.
3. Biomarkers are significantly elevated in patients, indicating increased collagen turnover and inflammation.

Keyword: Collagen degradation, MMPs (Matrix metalloproteinases), TIMP-1 (Tissue inhibitor of metalloproteinases), CTX (C-terminal telopeptide of collagen), Chronic inflammation, Connective tissue disorders

Introduction

Collagen is a fundamental protein in the human body, being the primary structural component in connective tissues including skin, cartilage, tendons, ligaments, and bones. It gives strength, elasticity, and structural stability to several tissues [1]. Collagen degradation is an intrinsic process that takes place at some point as a part of the rearrangement and restoration of the tissue; even so, when this process is deregulated, it can be involved in diverse pathological situations such as connective tissue diseases and chronic inflammatory disorders. The growth of tissues associated with collagen degradation has become important in the diagnosis and monitoring of these conditions and possibly the development of therapeutic interventions [2]. Connective tissue disorders are diseases associated with loss of integrity and function of connective tissues. These disorders may be hereditary or sporadic and are often characterized by defects in collagen synthesis, cleavage, or turnover. The usual ones are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, osteoarthritis (OA), and other various inflammatory diseases that affect the internal organs, skin and joints. Both of these processes, turned on in these environments of excessive or insufficient collagen degradation, can ultimately result in joint damage, fibrosis, and organ dysfunction [3]. The immune system, when activated persistently, participates in the damage and remodeling of the tissue, thus making chronic inflammation a common factor in the progression of connective tissue diseases [4]. Collagen degradation is a relatively complex procedure that involves several of the different enzymes, especially matrix metalloproteinases (MMP). Fibroblasts, neutrophils, macrophages, and other cell types secrete these enzymes in response to inflammatory signals. Among 22 known MMPs, especially MMP-1 (collagenase) and MMP-9 (gelatinase), degrade collagen fibrils and extracellular matrix (ECM) and promote tissue remodeling. However, overactivity or deregulation of these enzymes may result in an overactivity of collagen degradation, causing destruction of the tissues and inflammation [5,6]. A major mechanism of collagen resolution derives from an equilibrium between a family of matrix metalloproteinases (MMPs) and their tissue inhibitors, referred to as the tissue inhibitors of metalloproteinases (TIMPs). Tissue inhibitors of metalloproteinases (TIMPs), particularly TIMP-1, suppress MMP activity and prevent excessive degradation of collagen and extracellular matrix (ECM) components [7]. An imbalance in either direction (increased MMP activity vs. decreased TIMP activity) underlies some of the abnormal structural remodeling that characterizes connective tissue disorders and chronic inflammation. For example, remodeling of the ECM in diseases such as rheumatoid arthritis and osteoarthritis is accompanied by elevated levels of MMPs and reduced levels of tissue inhibitors of metalloproteinases (TIMPs), with joint tissue degradation reflected in cartilage destruction and bone erosion [8,9]. The C-terminal telopeptide of type I collagen (CTX) is another relevant biomarker of collagen degradation. CTX is a fragment produced during the degradation of collagen fibers in bone and other connective tissues. In addition to established roles as a sensitive marker of bone resorption in diseases like osteoporosis, it has recently been identified as a key player in other connective tissue diseases, especially in chronic inflammatory diseases [10]. CTX high concentrations indicate increased collagen degradation during active tissue remodeling and can be a marker of diseases with active tissue remodeling and inflammation [11]. Inflammatory cytokines are also involved in that pathway concerning collagen degradation. We know that tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are cytokines that cause inflammation and are very important in turning on MMP and stopping collagen production. TNF-α is one of the main factors that causes inflammation because it makes MMPs come out and breaks down the extracellular matrix (ECM). Some researchers, including Maas et al., say that ongoing epithelial tissue damage is caused by these pathways being activated over and over again, which leads to chronic inflammation that is seen in diseases like rheumatoid arthritis and systemic lupus erythematosus [12]. For this reason, people have been looking for early signs of disease, like cytokines and biomarkers of collagen breakdown (MMPs, TIMPs, and CTX). These are useful for diagnosing and predicting connective tissue illnesses. Now, biomarkers like C-reactive protein can help doctors figure out which people have current disease and how bad it is and how fast it is spreading. They could also be used as a target for therapy. Inhibition of MMP activity or modulation of TIMP and inflammatory cytokine levels may be a valuable target for key approaches for therapeutic strategies for prevention or delay of connective tissue damage in chronic inflammation [13,14]. This study investigates the levels of biomarkers of collagen degradation (MMP-1, MMP-9, TIMP-1, C-terminal telopeptide of collagen (CTX), C-reactive protein (CRP), and Tumor Necrosis Factor-alpha (TNF-α) in patients with connective tissue disorders and chronic inflammation (rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus) and healthy controls. This study seeks to explore the potential significance of these biomarkers in the pathogenesis and advancement of connective tissue damage, thus providing important epidemiological information on their diagnostic and prognostic applications in these disorders.

Methods

The current study was designed as a comparative cross-sectional analysis of collagen degradation biomarkers, which were assessed in cases of connective tissue disorders with chronic inflammation, namely, rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus. A total of 75 patients with these symptoms were enrolled as well as 50 healthy controls. Sociodemographic data, including age, gender, BMI, and smoking status, were obtained. After overnight fast, blood samples were collected from participants, and plasma samples used to measure key biomarkers, including MMP-1, MMP-9, TIMP-1, C-terminal telopeptide of collagen (CTX), C-reactive protein (CRP), and Tumor Necrosis Factor-alpha (TNF-α) using ELISA assays. Blood samples were drawn by venipuncture and collected in respective tubes, and serum was separated by centrifugation at 3000 rpm for 10 minutes. Serum samples were aliquoted and stored at −80°C until use. ELISA tests were conducted following the manufacturer’s instructions with Bio-Techne, USA kits. Biopsy samples were processed by standard tissue processing methods and stained by appropriate methods, including Hematoxylin and Eosin (H&E) for tissue structure and Masson’s Trichrome for collagen. Inclusion criteria were patients aged 18–70 years and a clinical diagnosis of connective tissue disorders, and exclusion criteria were active infections, malignant tumors, or other autoimmune diseases. Ethical Approval The study was approved by the institutional review board, and all patients signed a consent form for informed consent. The study was performed from January 5, 2025, to March 5, 2025, in Al-Habboubi Teaching Hospital and Al-Nasiriyah General Hospital.

Statistical analysis :

Data analysis was performed using SPSS 26.0 (IBM, USA), with descriptive statistics presented as mean ± standard deviation (SD) for continuous variables and frequencies with percentages for categorical variables. The Shapiro-Wilk test assessed data normality, followed by one-way ANOVA or the Kruskal-Wallis test to compare biomarker levels among patient groups and controls, with Tukey’s post hoc test or Dunn’s test with Bonferroni correction for pairwise comparisons. Pearson’s or Spearman’s correlation was used based on data distribution, and multivariate linear regression identified predictors of collagen degradation biomarkers, adjusting for confounding factors such as age, BMI, and smoking status. A p-value < 0.05 was considered statistically significant.

Ethical approval:

The study received ethical approval from the human ethics committees of Al-Habboubi Teaching Hospital and Al-Nasiriyah General Hospital. Informed consent was obtained from all participants after providing a detailed explanation of the study's purpose and procedures. Participants were also assured that their personal information would remain confidential and accessible only to the research team.

Results and Discussion

Result

Baseline Sociodemographic Characteristics of Study Participants

People in the healthy group were 48.7 ± 9.2 years old, while people in the sick group were 52.3 ± 10.5 years old on average. There was no statistically significant difference between the two groups (P = 0.081). In terms of gender breakdown, 56% of the cases were men and 44% were women. In contrast, 54% of the healthy people were men and 46% were women, and the difference was not statistically significant (P = 0.792). There was a statistically significant difference (P = 0.003) between the patient group's mean body mass index (BMI) and the healthy group's (25.4 ± 3.1 kg/m²). The patient group's BMI was significantly higher than the healthy group's. It was found that 41% of the patients smoked, compared to 28% of the healthy people. However, the difference was not statistically significant (P = 0.118). These results show that there may be a link between being overweight and connective tissue disorders. More study is needed to find out how demographic factors affect the growth of diseases as shown in the table 1.

Collagen Degradation Biomarkers in Patients and Healthy Controls

The results showed that MMP-1 levels were significantly higher in the patient group (8.2 ± 2.1 ng/ml) compared to healthy controls (4.6 ± 1.3 ng/ml), with a statistically significant difference (P < 0.001). MMP-9 levels were also higher in patients (57.3 ± 12.5 ng/ml) compared to healthy controls (32.8 ± 8.7 ng/ml), with a statistically significant difference (P < 0.001). TIMP-1 and patients had a significantly higher level compared to healthy participants (234.5 ± 34.2 ng/ml compared to 198.7 ± 25.8 ng/ml, P = 0.002). C-terminal Telopeptide of Collagen (CTX) levels were increased in patients compared with healthy controls (3.9 ± 0.8 ng/ml versus 2.1 ± 0.6 ng/ml, P < 0.001). Earlier studies showed elevated CTX levels in patients, confirming greater activity of collagenase enzymes (MMPs) indicative of a higher rate of collagen degradation in connective tissue disorders and chronic inflammation as shown in the table 2.

Inflammatory Biomarkers in Patients and Healthy Controls

Patients had significantly higher C-reactive protein (CRP) levels (10.4 ± 3.5 mg/L) than healthy controls (3.8 ± 1.2 mg/L); the difference was statistically significant (P < 0.001). TNF-α was also statistically significantly increased in patients (18.6 ± 4.2 pg/mL versus 12.1 ± 3.1 pg/mL in healthy controls, P < 0.001). Chronic inflammation seems to play a role in connective tissue disorders, as these results show a distinct increase in inflammatory markers in patients as shown in the table 3.

Figure 1.Histological Section of a Rheumatoid Arthritis-Affected Joint (H&E Staining, 40x)

Figure 1 shows a histopathological section of a joint affected by rheumatoid arthritis, stained with Hematoxylin and Eosin (H&E). The section reveals characteristic pathological changes, including synovial hyperplasia, inflammatory cell infiltration, and cartilage degradation. Notably, the synovial membrane appears thickened with increased cellularity, indicating an inflammatory response. Erosion of the cartilage and subchondral bone is visible, suggesting progressive joint destruction due to excessive collagen degradation. The presence of inflammatory infiltrates, primarily composed of lymphocytes and macrophages, is indicative of chronic inflammation. These findings align with the study’s results, which highlight elevated biomarkers such as MMP-1, MMP-9, TIMP-1, and CTX, reflecting increased collagen turnover and tissue remodeling in rheumatoid arthritis.

Figure 2.Histological Section of Cartilage and Bone in Osteoarthritis (Safranin O Staining, 100x)

Figure 2 represents a histopathological section of osteoarthritic cartilage and bone, stained with Safranin O. The staining highlights the distribution and degradation of proteoglycans within the cartilage matrix, with a distinct color gradient indicating areas of cartilage erosion. The image shows notable structural changes, including chondrocyte clustering, loss of cartilage matrix, and subchondral bone remodeling. Fissures and clefts in the cartilage surface are visible, indicative of progressive degeneration. The presence of adipose infiltration and inflammatory changes further suggests joint deterioration. These findings align with the study’s biochemical results, which reported elevated levels of collagen degradation biomarkers (MMP-1, MMP-9, TIMP-1, CTX) and inflammatory markers (CRP, TNF-α), confirming increased collagen turnover and tissue remodeling in osteoarthritis.

Figure 3.Histological Section of Kidney Tissue (PAS Staining, 100x)

Figure 3 represents a kidney tissue section stained with Periodic Acid-Schiff (PAS) staining. The staining highlights basement membrane components and glycogen deposits, which are critical in assessing structural alterations in renal pathology. The image reveals glomerular abnormalities, including thickening of the basement membrane and mesangial expansion, which are indicative of chronic inflammation and potential fibrotic changes. Tubular atrophy and interstitial fibrosis are evident, suggesting ongoing tissue remodeling processes. The presence of these pathological changes aligns with the study’s findings on increased collagen degradation and inflammatory biomarkers (MMPs, TIMP-1, CTX, CRP, TNF-α), indicating systemic involvement of connective tissue disorders affecting multiple organs.

Figure 4.Histological Section of Collagen degredation (PAS Staining, 100x)

Figure 4 represents a histopathological section of connective tissue affected by collagen degradation, stained with Periodic Acid-Schiff (PAS) staining. The staining highlights extracellular matrix components, showing disrupted collagen fibers and areas of increased cellular infiltration. The presence of irregular and fragmented collagen bundles indicates excessive matrix remodeling, which is characteristic of chronic inflammatory and connective tissue disorders. The scattered fibroblast proliferation, along with inflammatory cell infiltration, suggests an ongoing tissue repair and degradation process. These histopathological findings correlate with the study’s biochemical results, which demonstrated elevated collagen degradation biomarkers (MMP-1, MMP-9, TIMP-1, CTX) and inflammatory markers (CRP, TNF-α), confirming increased collagen turnover and chronic inflammation in connective tissue disorders.

Discussion

Table 1 shows significant differences in some sociodemographic characteristics between connective tissue disorders and chronic inflammation patients compared to healthy controlsJ. In particular, the mean age of the cases was higher than that of the healthy controls. However, the difference was not statistically significant (P = 0.081), which means that age is not a major cause of the changes seen in biomarkers. The percentage of men and women in the two groups was almost the same (56% men and 44% women in the cases and 54% men and 46% women in the controls. The difference between the groups was not significant (P-value = 0.792), which means that gender did not play a role in this study. The biggest difference was seen in BMI, where the patient's mean BMI was 27.8 ± 3.6 kg/m², and the healthy groups' mean BMI was 25.4 ± 3.1 kg/m² (P-value = 0.003). This finding is consistent with obesity often being associated with chronic inflammation and driving or promoting the development of connective tissue disorders like RA and OA, given that increased BMI leads to higher levels of systemic inflammation. With respect to smoking status, while more patients (41%) were smokers than healthy controls (28%), this did not reach statistical significance (P-value = 0.118), indicating that smoking is not likely to be a significant contributor to the difference observed in [15], smoking was was found to put patients at greater risk for exacerbating inflammation in rheumatoid arthritis etube, but this did not influence the results in the present study appreciably [16]. The differences observed, particularly in relation to BMI, may be related to the pathophysiological association between obesity and inflammation, since adipose tissue increases the production of pro-inflammatory cytokines that could worsen the scenario of patients with connective tissue diseases [17]. f note, the differences in levels of collagen degradation biomarkers in patients frequently compare healthy controls and patients with connective tissue disorders and chronic inflammation (Table 2). In particular, MMP-1, MMP-9, TIMP-1, and CTX levels were markedly elevated in the patients versus the healthy controls (P-values were <0.001 for both MMP-1 and MMP-9MMP-9, CTX, and 0.002 for TIMP-1). Similar to previous studies, they have shown high levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in chronic inflammation or connective tissue disease patients. Badulescu et al.(2024) so showed significantly elevated levels of MMP-9 in rheumatoid arthritis patients when compared to controls, consistent with our findings [18]. Furthermore,, Batty et al.(2024) ported increased MMP-1 and TIMP-1 in osteoarthritis patients, while also sustaining our finding of increased MMP-1 and TIMP-1 in the patient group [19]. Taking the first study,, Jarecki et al.(2022), as an example, some studies found no statistically significant difference in MMP levels; differences in patient selection criteria or assay methods may underlie differences in results [20]. In patients, these biomarkers show higher levels, which may be due to the inflammatory processes of the underlying connective tissue disorders, in which MMPs are excessively produced to degrade components from the extracellular matrix, while the increased levels of TIMPs represent a counter-regulatory response [21]. Higher CTX levels were noted in patients, consistent with an elevated collagen turnover, which occurred with tissue destruction in these diseases. Factors contributing to the differences in the findings reported from different studies could also include heterogeneous disease stages and therapeutic modalities tested and different sensitivity of detection assays [22,23]. The data in Table 3 again showed a statistically significant increase in study cases of C-Reactive Protein (CRP) and Tumor Necrosis Factor-alpha (TNF-α) compared with healthy control. In particular, higher levels of CRP were observed in patients (10.4 ± 3.5 mg/L) than in healthy controls (3.8 ± 1.2 mg/L) with P < 0.001. In parallel, TNF-α levels were also significantly higher in patients (18.6 ± 4.2 pg/mL) than in controls (12.1 ± 3.1 pg/mL) (P < 0.001). CRP and TNF-α markers are all widely recognized as markers of inflammation and consistent with these findings. CRP is an acute-phase protein produced in response to pro-inflammatory cytokines like TNF-α, making patients with chronic inflammation likely to have high levels of CRP in their blood. Such studies support findings similar to Stanimirovic et al. (2022), who found that patients with rheumatoid arthritis had significantly elevated levels of CRP and TNF-α, mirroring our results [24]. Additionally, Saleh et al. (2022) identified higher TNF-α levels among patients with systemic lupus erythematosus, which support the increased TNF-α levels detected in our study [25]. However, studies like that of Yi et al. (2022) described lower levels of TNF-α and CRP increases, potentially resulting from differences between patient cohorts, duration of T-cell dysregulation, or medication use, both of which may alter inflammatory markers [26]. Increased levels of CRP and TNF-α have been found in our study; thus, they are pathognomonic in this cohort of patients that are prone to have an active inflammatory process in the course of connective tissue disorder, indicating the emergent role of TNF-α in the onset and progression of the inflammatory cascade while CRP is simply the circulating marker of this inflammation that is underway [27]. Differences in severity of the disease, ethnic differences, and methods used for the analysis of these biomarkers may also be responsible for the disparity of the results [26,27].

Conclusion

The study concludes that elevated levels of collagen degradation biomarkers (MMP-1, MMP-9, TIMP-1, CTX) and inflammatory markers (CRP, TNF-α) in patients with connective tissue disorders suggest increased collagen turnover and chronic inflammation. MMPs are enzymes that degrade collagen, and their elevated levels indicate heightened tissue remodeling, contributing to tissue damage. TIMP-1, an inhibitor of MMPs, showed a relative increase, reflecting a compensatory mechanism. The elevated CRP and TNF-α levels signify ongoing systemic inflammation, further promoting disease progression and contributing to the breakdown of connective tissue.

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