Comparison between RA, OA, and HA
| . | RA . | OA . | HA . |
|---|---|---|---|
| Initiation | Inflammatory joint lesions caused due to an autoimmune response (e.g. citrullination, infection). “Second hit” may be required. Antigen presentation promotes antibody generation in B cells. Reviewed by Smolen et al.77 | Degenerative joint injury is caused by multiple factors, including aging, direct injury, and biomechanical overloading. These events alter articular cartilage, subchondral bone, ligaments, capsule, and synovial membrane that culminate in joint failure. Reviewed by Martel-Pelletier et al.78 | Degenerative joint damage as seen in OA as well as chronic inflammation as in RA. Synovial lesions triggered by iron deposition due to bleeding in the joint that activates proteases and inflammatory cytokines. Reviewed by Zhu et al.79 |
| Intraarticular mechanisms | 1) Synovial tissue proliferation as an inflammatory response, resulting in the production of IL1, IL-6, TNF, MMPs, prostaglandins, and RANKL. Cartilage invasion from invasive synovial tissue (pannus) occurs. 2) Cartilage damage is caused by proteases (eg, MMPs, aggrecanases, collagenases, and stromelysins). 3) Propagation of inflammation by antigen-presenting cells, lymphocytes, and macrophages, producing CCL19, CCL21, TNF, IL1, IL6, and RANKL. 4) Bone erosion via activation of osteoclasts by RANKL by IL1 and IL6. Reviewed by Smolen et al.77 | 1) Chondrocyte and synovial activation through cytokines, including DAMPs, IL-1β, CCL19, TNFα, IL15, and MCP-1. 2) Activated chondrocytes produce proteases, including MMPs, aggrecanases, serine, and cysteine proteinases. Extracellular matrix fragments further stimulate synovial cells. 3) Bone remodeling through TGF β, BMP2, IL6, IL8, and RANKL results in osteophyte formation. Reviewed by Martel-Pelletier et al.78 | 1) Synovial tissue is stimulated through iron to produce IL1β, IL6, TNFα, CCL2 and CXCL1, MMPs, and aggrecanases. 2) Iron causes direct damage to cartilage by reacting with H2O2 to produce reactive oxygen species, in addition to propagating inflammation through IL1β, IL6, and TNFα. Subsequently, monocytes/macrophages, neutrophils, and activated T cells are recruited to the site of bleeding. 3) Tissue hyperplasia promotes neoangiogenesis. The instability of new vessels formed further increases the risk of intraarticular hemorrhage. 4) Bone degeneration progresses more rapidly and severely than RA and OA. Bone turnover is likely mediated by RANKL/ osteoprotegerin and Wnt/β-catenin signaling pathways. Reviewed by Zhu et al.79 |
| MMP involvement | |||
| MMP-1 | Levels correlate with the degree of synovial inflammation in the joint in RA.80 | Upregulated in joint fluid but not as high as that seen in RA.42 High expression in chondrocytes cultured from OA patient cartilage explants.81 | Expression detected in ligaments of patients.45 |
| MMP-2 | Patients with erosive disease have higher synovial active MMP-2 levels, strongly implicating MMP-2 in synovial tissue as a marker for aggressive synovitis.43 Although MMP-2 is upregulated in arthritic joints, MMP-2–deficient mice are more susceptible to antibody-induced arthritis, indicating that MMP-2 may play a suppressive role in the progression of arthritis, possibly due to its ability to cleave and inactivate IL-17, that regulates migration and invasion and inflammation of RA synovial fibroblasts.57 | MMP-2 expression in the ECM of subchondral bone during OA causes degradation of type I and other fibrillar collagens, and increased collagen turnover potentiates cartilage damage that affects joint morphology, thereby worsening OA.82 Immunopositive staining in plica and pannus-like tissue of late-stage OA knee joints.50 | Expression detected in ligaments of patients.45 |
| MMP-3 | Strongly expressed in the joint cavities in patients with RA.36 Correlates with disease severity.74 Upregulated in the early–mid stages of RA.74 | Immunopositive chondrocytes are visible in the superficial zone in human articular cartilage tissue.83 | Expression detected in ligaments of patients.45 Expression induced after knee injury in F8−/− mice.84 |
| MMP-8 | Protective, as deficiency leads to enhanced synovial inflammation and bone degradation in a mouse model.85 | Immunopositive chondrocytes are visible in the superficial zone in human articular cartilage tissue.83 | Increased expression in an autologous blood injection mouse model of HA.47 |
| MMP-9 | Mice deficient in MMP-9 are less severely affected in a model of antibody-induced arthritis.57 | Increased; MMP-9 levels correlate with synovial fluid VEGF levels implicating MMP-9 in the regulation of angiogenesis during OA.42 Immunopositive staining in plica and pannus-like tissue of late-stage OA knee joints.50 | High and moderate expression in the vascular endothelium and in synovial cells, respectively, in human tissue.49 |
| MMP-10 | Strongly expressed in synovial fluid.63 Under inflammatory conditions, both synovial fibroblasts and articular chondrocytes express MMP-10.63 Further able to activate procollagenases, including MMP-1, -8, and -13, which also promote cartilage degradation.63 | Strongly expressed in synovial fluid.63 | No involvement documented to date. |
| MMP-13 | Implicated in RA-associated joint disease—degrades collagen II and aggrecan.36 MMP-13 increased in joint fluid of RA patients.74 High immunopositivity staining in synovium correlates with severity of inflammation.75 Suppression associated with joint protection in a mouse model.86 | Critical role in induction and pathogenesis. Degrades articular cartilage and triggers synovial hyperplasia, synovitis with marked immune cells infiltration in synovial joints, as well as cartilage erosion.40 Immunopositive chondrocytes are visible in the superficial zone in human articular cartilage tissue.83 Associated with structural cartilage damage in a rodent model of OA.87 | Expression induced after knee injury in F8−/− mice.84 |
| MMP-14 (MT-MMP1), activator for pro–MMP-2 | Significantly higher, and TIMP-2 expression was reduced in synovial tissue.43 | Highly expressed in chondrocytes during OA.62 | No involvement documented to date. |
| . | RA . | OA . | HA . |
|---|---|---|---|
| Initiation | Inflammatory joint lesions caused due to an autoimmune response (e.g. citrullination, infection). “Second hit” may be required. Antigen presentation promotes antibody generation in B cells. Reviewed by Smolen et al.77 | Degenerative joint injury is caused by multiple factors, including aging, direct injury, and biomechanical overloading. These events alter articular cartilage, subchondral bone, ligaments, capsule, and synovial membrane that culminate in joint failure. Reviewed by Martel-Pelletier et al.78 | Degenerative joint damage as seen in OA as well as chronic inflammation as in RA. Synovial lesions triggered by iron deposition due to bleeding in the joint that activates proteases and inflammatory cytokines. Reviewed by Zhu et al.79 |
| Intraarticular mechanisms | 1) Synovial tissue proliferation as an inflammatory response, resulting in the production of IL1, IL-6, TNF, MMPs, prostaglandins, and RANKL. Cartilage invasion from invasive synovial tissue (pannus) occurs. 2) Cartilage damage is caused by proteases (eg, MMPs, aggrecanases, collagenases, and stromelysins). 3) Propagation of inflammation by antigen-presenting cells, lymphocytes, and macrophages, producing CCL19, CCL21, TNF, IL1, IL6, and RANKL. 4) Bone erosion via activation of osteoclasts by RANKL by IL1 and IL6. Reviewed by Smolen et al.77 | 1) Chondrocyte and synovial activation through cytokines, including DAMPs, IL-1β, CCL19, TNFα, IL15, and MCP-1. 2) Activated chondrocytes produce proteases, including MMPs, aggrecanases, serine, and cysteine proteinases. Extracellular matrix fragments further stimulate synovial cells. 3) Bone remodeling through TGF β, BMP2, IL6, IL8, and RANKL results in osteophyte formation. Reviewed by Martel-Pelletier et al.78 | 1) Synovial tissue is stimulated through iron to produce IL1β, IL6, TNFα, CCL2 and CXCL1, MMPs, and aggrecanases. 2) Iron causes direct damage to cartilage by reacting with H2O2 to produce reactive oxygen species, in addition to propagating inflammation through IL1β, IL6, and TNFα. Subsequently, monocytes/macrophages, neutrophils, and activated T cells are recruited to the site of bleeding. 3) Tissue hyperplasia promotes neoangiogenesis. The instability of new vessels formed further increases the risk of intraarticular hemorrhage. 4) Bone degeneration progresses more rapidly and severely than RA and OA. Bone turnover is likely mediated by RANKL/ osteoprotegerin and Wnt/β-catenin signaling pathways. Reviewed by Zhu et al.79 |
| MMP involvement | |||
| MMP-1 | Levels correlate with the degree of synovial inflammation in the joint in RA.80 | Upregulated in joint fluid but not as high as that seen in RA.42 High expression in chondrocytes cultured from OA patient cartilage explants.81 | Expression detected in ligaments of patients.45 |
| MMP-2 | Patients with erosive disease have higher synovial active MMP-2 levels, strongly implicating MMP-2 in synovial tissue as a marker for aggressive synovitis.43 Although MMP-2 is upregulated in arthritic joints, MMP-2–deficient mice are more susceptible to antibody-induced arthritis, indicating that MMP-2 may play a suppressive role in the progression of arthritis, possibly due to its ability to cleave and inactivate IL-17, that regulates migration and invasion and inflammation of RA synovial fibroblasts.57 | MMP-2 expression in the ECM of subchondral bone during OA causes degradation of type I and other fibrillar collagens, and increased collagen turnover potentiates cartilage damage that affects joint morphology, thereby worsening OA.82 Immunopositive staining in plica and pannus-like tissue of late-stage OA knee joints.50 | Expression detected in ligaments of patients.45 |
| MMP-3 | Strongly expressed in the joint cavities in patients with RA.36 Correlates with disease severity.74 Upregulated in the early–mid stages of RA.74 | Immunopositive chondrocytes are visible in the superficial zone in human articular cartilage tissue.83 | Expression detected in ligaments of patients.45 Expression induced after knee injury in F8−/− mice.84 |
| MMP-8 | Protective, as deficiency leads to enhanced synovial inflammation and bone degradation in a mouse model.85 | Immunopositive chondrocytes are visible in the superficial zone in human articular cartilage tissue.83 | Increased expression in an autologous blood injection mouse model of HA.47 |
| MMP-9 | Mice deficient in MMP-9 are less severely affected in a model of antibody-induced arthritis.57 | Increased; MMP-9 levels correlate with synovial fluid VEGF levels implicating MMP-9 in the regulation of angiogenesis during OA.42 Immunopositive staining in plica and pannus-like tissue of late-stage OA knee joints.50 | High and moderate expression in the vascular endothelium and in synovial cells, respectively, in human tissue.49 |
| MMP-10 | Strongly expressed in synovial fluid.63 Under inflammatory conditions, both synovial fibroblasts and articular chondrocytes express MMP-10.63 Further able to activate procollagenases, including MMP-1, -8, and -13, which also promote cartilage degradation.63 | Strongly expressed in synovial fluid.63 | No involvement documented to date. |
| MMP-13 | Implicated in RA-associated joint disease—degrades collagen II and aggrecan.36 MMP-13 increased in joint fluid of RA patients.74 High immunopositivity staining in synovium correlates with severity of inflammation.75 Suppression associated with joint protection in a mouse model.86 | Critical role in induction and pathogenesis. Degrades articular cartilage and triggers synovial hyperplasia, synovitis with marked immune cells infiltration in synovial joints, as well as cartilage erosion.40 Immunopositive chondrocytes are visible in the superficial zone in human articular cartilage tissue.83 Associated with structural cartilage damage in a rodent model of OA.87 | Expression induced after knee injury in F8−/− mice.84 |
| MMP-14 (MT-MMP1), activator for pro–MMP-2 | Significantly higher, and TIMP-2 expression was reduced in synovial tissue.43 | Highly expressed in chondrocytes during OA.62 | No involvement documented to date. |
These conditions have different triggers and hypothesized initiation factors. However, an overlapping pathology is seen through inflammatory processes, resulting in changes to synovium, cartilage, and bone that result in an increase in similar tissue-modifying proteins that lead to articular cartilage and bone damage as a common consequence.
CCLs, chemokine ligand; MCP1, monocyte chemotactic protein 1; RANKL, receptor activator of nuclear factor κ B ligand.