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Comparative study on the effect of ankylosing spondylitis and rheumatoid arthritis on the bone
Comparative study on the effect of ankylosing spondylitis and rheumatoid arthritis on the bone
I am a PhD student in Biomedical Sciences at the Rheumatology Research Unit of the Institute of Molecular Medicine of the Faculty of Medicine of the University of Lisbon. I am studying bone biology, specifically the formation and function of osteoclasts, the cells responsible for bone destruction. In my work, I am also interested in the relationship between the bone and the immune system and cellular interactions in bone formation and resorption, particularly in chronic inflammatory diseases.
Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS) are both systemic, chronic and immune-mediated diseases that primarily affect peripheral joints, as in the case of RA, and the axial skeleton and entheses, in the case of AS. These diseases present some differences in terms of genetic predisposition and clinical presentation, but share common pathogenic pathways, such as the involvement of TNF and IL-17-.
In RA inflammation originates in the synovial membrane of peripheral joints, which will trigger the appearance of bone erosions. In the case of AS, there is inflammation of the axial skeleton and sacroiliac joints, with bone formation and subsequent fusion. The enthesis or the subchondral bone are the primary site of inflammation, with oedema, lymphocytic infiltration and increased microvascular intensity. The outcome of both diseases is defined at the level of structural damage. Whereas RA is associated with destruction (erosions, narrowed joint space), AS is associated with bone formation (syndesmophytes).
The treatment of both diseases shares some similarities: non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARDs, such as methotrexate) and tumour necrosis factor (TNF) antagonists. However, the response to conventional DMARDs is higher in RA than in AS, and for RA there are also other drugs that are effective but which do not work properly in AS (such as abatacept, rituximab and tocilizumab).
Bone tissue is one of the main tissues affected in both diseases. In a normal situation, the bone is constantly changing through two types of cells: osteoblasts responsible for bone formation, and osteoclasts responsible for bone resorption. Osteoblasts are responsible for the formation, deposition and mineralization of bone tissue. On the other hand, osteoclasts, which are responsible for bone resorption, result from the differentiation of mononuclear precursors from the lineage of monocytes/macrophages in bone marrow and peripheral circulation.
Monocytes fuse giving rise to multinucleated giant cells - pre-osteoclasts - which undergo a series of morphological changes culminating in the formation of a ruffled membrane that is characteristic of osteoclasts. Osteoclasts are essential for the normal development of the skeleton to maintain its integrity and calcium metabolism. For bone resorption to occur, they bind to the bone matrix through integrin binding to specific components of the bone, such as osteopontin and vitronectin; they organize the cytoskeleton, taking up a polarized morphology and forming a ruffled membrane for the secretion of acid and enzymes, creating an isolated environment – the resorption lacuna. The survival of osteoclasts and their involvement in successive cycles of bone resorption is regulated by hormones and cytokines, and by osteoblasts.
It is believed that bone remodelling begins with the formation of the resorption lacuna by activated osteoclasts, followed by the activation of osteoblasts that fill the lacuna with new bone matrix. In pathological conditions, the balance between resorption and formation may be lost, leading to changes in bone metabolism.
Several studies suggest that osteoclasts and the cells of the immune system are regulated by a large number of molecules, including cytokines, receptors, signalling molecules and transcription factors. In case of immune system hyperactivation, as is the case of RA, the risk of bone resorption is higher, and therefore of joint destruction. The pro-inflammatory cytokines stimulate the activity of osteoclasts. In vitro studies show that the IL-1, IL-6, IL-17 cytokines and TNF potentiate osteoclastogenesis directly through receptors present in osteoclasts and may thus lead to joint destruction.
The aim of my PhD is to understand how system inflammation promotes bone resorption in RA and bone formation in AS. Our hypothesis is that there are differences in osteoclastogenesis between RA and AS, and accordingly, the objectives of this study are: to determine the osteoclastogenic stimulus, characterize osteoclast precursors and compare the differentiation of osteoclasts in patients with RA and AS.
Preliminary results suggest that AS patients do not differ from controls with regard to surface RANKL expression. AS patients have less RANK expression at the surface of OC precursors when compared with controls. Finally, we detected a reduced expression of key genes during differentiation in OC in patients with AS when compared with controls. These findings suggest an impairment of OC differentiation in patients with AS that may contribute to the observed bone forming phenotype.
Inês Perpétuo
PhD student
I am a PhD student in Biomedical Sciences at the Rheumatology Research Unit of the Institute of Molecular Medicine of the Faculty of Medicine of the University of Lisbon. I am studying bone biology, specifically the formation and function of osteoclasts, the cells responsible for bone destruction. In my work, I am also interested in the relationship between the bone and the immune system and cellular interactions in bone formation and resorption, particularly in chronic inflammatory diseases.
Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS) are both systemic, chronic and immune-mediated diseases that primarily affect peripheral joints, as in the case of RA, and the axial skeleton and entheses, in the case of AS. These diseases present some differences in terms of genetic predisposition and clinical presentation, but share common pathogenic pathways, such as the involvement of TNF and IL-17-.
In RA inflammation originates in the synovial membrane of peripheral joints, which will trigger the appearance of bone erosions. In the case of AS, there is inflammation of the axial skeleton and sacroiliac joints, with bone formation and subsequent fusion. The enthesis or the subchondral bone are the primary site of inflammation, with oedema, lymphocytic infiltration and increased microvascular intensity. The outcome of both diseases is defined at the level of structural damage. Whereas RA is associated with destruction (erosions, narrowed joint space), AS is associated with bone formation (syndesmophytes).
The treatment of both diseases shares some similarities: non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARDs, such as methotrexate) and tumour necrosis factor (TNF) antagonists. However, the response to conventional DMARDs is higher in RA than in AS, and for RA there are also other drugs that are effective but which do not work properly in AS (such as abatacept, rituximab and tocilizumab).
Bone tissue is one of the main tissues affected in both diseases. In a normal situation, the bone is constantly changing through two types of cells: osteoblasts responsible for bone formation, and osteoclasts responsible for bone resorption. Osteoblasts are responsible for the formation, deposition and mineralization of bone tissue. On the other hand, osteoclasts, which are responsible for bone resorption, result from the differentiation of mononuclear precursors from the lineage of monocytes/macrophages in bone marrow and peripheral circulation.
Monocytes fuse giving rise to multinucleated giant cells - pre-osteoclasts - which undergo a series of morphological changes culminating in the formation of a ruffled membrane that is characteristic of osteoclasts. Osteoclasts are essential for the normal development of the skeleton to maintain its integrity and calcium metabolism. For bone resorption to occur, they bind to the bone matrix through integrin binding to specific components of the bone, such as osteopontin and vitronectin; they organize the cytoskeleton, taking up a polarized morphology and forming a ruffled membrane for the secretion of acid and enzymes, creating an isolated environment – the resorption lacuna. The survival of osteoclasts and their involvement in successive cycles of bone resorption is regulated by hormones and cytokines, and by osteoblasts.
It is believed that bone remodelling begins with the formation of the resorption lacuna by activated osteoclasts, followed by the activation of osteoblasts that fill the lacuna with new bone matrix. In pathological conditions, the balance between resorption and formation may be lost, leading to changes in bone metabolism.
Several studies suggest that osteoclasts and the cells of the immune system are regulated by a large number of molecules, including cytokines, receptors, signalling molecules and transcription factors. In case of immune system hyperactivation, as is the case of RA, the risk of bone resorption is higher, and therefore of joint destruction. The pro-inflammatory cytokines stimulate the activity of osteoclasts. In vitro studies show that the IL-1, IL-6, IL-17 cytokines and TNF potentiate osteoclastogenesis directly through receptors present in osteoclasts and may thus lead to joint destruction.
The aim of my PhD is to understand how system inflammation promotes bone resorption in RA and bone formation in AS. Our hypothesis is that there are differences in osteoclastogenesis between RA and AS, and accordingly, the objectives of this study are: to determine the osteoclastogenic stimulus, characterize osteoclast precursors and compare the differentiation of osteoclasts in patients with RA and AS.
Preliminary results suggest that AS patients do not differ from controls with regard to surface RANKL expression. AS patients have less RANK expression at the surface of OC precursors when compared with controls. Finally, we detected a reduced expression of key genes during differentiation in OC in patients with AS when compared with controls. These findings suggest an impairment of OC differentiation in patients with AS that may contribute to the observed bone forming phenotype.
Inês Perpétuo
PhD student
