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Paget's disease of bone: an osteoimmunological disorder?

Numan MS, Amiable N, Brown JP, Michou L - Drug Des Devel Ther (2015)

Bottom Line: Paget's disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation.The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders.As a potential osteoimmunological disorder, the treatment of Paget's disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition.

View Article: PubMed Central - PubMed

Affiliation: CHU de Québec Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada ; Division of Rheumatology, Department of Medicine, CHU de Québec-Université Laval, Quebec City, QC, Canada.

ABSTRACT
Osteoimmunology represents a large area of research resulting from the cross talk between bone and immune systems. Many cytokines and signaling cascades are involved in the field of osteoimmunology, originating from various cell types. The RANK/receptor activator of nuclear factor Kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling has a pivotal role in osteoimmunology, in addition to proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17. Clinically, osteoimmunological disorders, such as rheumatoid arthritis, osteoporosis, and periodontitis, should be classified according to their pattern of osteoimmunological serum biomarkers. Paget's disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation. With the exception of the cellular responses to measles virus nucleocapsid protein and the interferon-gamma signature, the exact role of the immune system in Paget's disease of bone is not well understood. The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders. As a potential osteoimmunological disorder, the treatment of Paget's disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition.

No MeSH data available.


Related in: MedlinePlus

Pathophysiology of Paget’s disease of bone and its relation to osteoimmunological cells and cytokines.Abbreviations: RANKL, Receptor Activator of Nuclear factor Kappa-B Ligand; TNF, Tumor Necrosis Factor-α; IFN, Interferon; MAPK, mitogen-activated protein kinase.
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f2-dddt-9-4695: Pathophysiology of Paget’s disease of bone and its relation to osteoimmunological cells and cytokines.Abbreviations: RANKL, Receptor Activator of Nuclear factor Kappa-B Ligand; TNF, Tumor Necrosis Factor-α; IFN, Interferon; MAPK, mitogen-activated protein kinase.

Mentions: IL-1 is a very essential cytokine in osteoimmunological processes. The analysis of supernatants from phytohemagglutinin-stimulated peripheral blood monocytes in healthy humans suggested that IL-1 acts as the main stimulus of osteoclast-activating factor, which has a central role in osteoclastogenic activity. Subsequently, the same bone resorbing stimulating activity was found in TNF-α and IL-6. Indeed, IL-1, IL-6, and TNF-α increase the osteoclasts response to RANKL and consequently osteolysis (Table 1). Estrogen withdrawal after menopause has the same stimulating effect, increasing osteoclastic activity through IL-1, IL-6, and TNF-α effects.18 Proinflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-17 (Table 1) are also elevated in patients with rheumatoid arthritis, contributing to increased RANKL expression and subsequent osteolysis.19 Schett et al have reviewed the important relation between autoimmunity and joint erosion in rheumatoid arthritis, revealing the presence of anti-citrullinated protein antibodies and anti-carbamylated protein antibodies in serum of the patients with rheumatoid arthritis. Molecular interaction between anti-citrullinated protein antibodies and the surface of osteoclast precursor cells via citrullinated vimentin induces differentiation and production of bone-resorbing osteoclasts, resulting in excessive bone resorption.20 Vitamin D3, prostaglandin E2, parathyroid hormone, in addition to IL-1, IL-6, IL-11, and TNF-α, can also induce RANKL expression, leading to excessive osteoclastogenesis (Figure 2).21 Activated T-cells were also reported to regulate bone loss and activation of osteoclastogenesis in vitro through RANKL.22 Contrariwise, TNF-stimulated gene 6 protein is an inflammation-induced protein that can inhibit osteoblastogenesis and osteoclast activation.23 In addition, immunoreceptor tyrosine-based activation motif (ITAM) pathway may contribute to the relationship between immune system and bone as a co-stimulatory pathway in osteoclasts. ITAM-dependent receptors regulate myeloid-derived cells functions. Furthermore, ITAM-containing adapter proteins such as DNAX activation protein-12 and the Fc epsilon receptor I gamma chain (FCER1G) play an essential role in osteoclast differentiation. Suppression of calcineurin–nuclear factor of activated T-cells signaling can reduce the activity of ITAM pathway in the late stage of osteoclast differentiation, leading to the reduction of osteoclast differentiation and activity.24,25 Calcium signaling induces the calmodulin-dependent kinase pathway role in osteoclast formation and plays a crucial role in the autoamplification of the transcription factor nuclear factor of activated T-cells cytoplasmic-1. Further, activation of TRAF6 and c-Fos pathways by RANKL leads to autoamplification of nuclear factor of activated T-cells cytoplasmic-1 and enhances osteoclastogenesis.21


Paget's disease of bone: an osteoimmunological disorder?

Numan MS, Amiable N, Brown JP, Michou L - Drug Des Devel Ther (2015)

Pathophysiology of Paget’s disease of bone and its relation to osteoimmunological cells and cytokines.Abbreviations: RANKL, Receptor Activator of Nuclear factor Kappa-B Ligand; TNF, Tumor Necrosis Factor-α; IFN, Interferon; MAPK, mitogen-activated protein kinase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544727&req=5

f2-dddt-9-4695: Pathophysiology of Paget’s disease of bone and its relation to osteoimmunological cells and cytokines.Abbreviations: RANKL, Receptor Activator of Nuclear factor Kappa-B Ligand; TNF, Tumor Necrosis Factor-α; IFN, Interferon; MAPK, mitogen-activated protein kinase.
Mentions: IL-1 is a very essential cytokine in osteoimmunological processes. The analysis of supernatants from phytohemagglutinin-stimulated peripheral blood monocytes in healthy humans suggested that IL-1 acts as the main stimulus of osteoclast-activating factor, which has a central role in osteoclastogenic activity. Subsequently, the same bone resorbing stimulating activity was found in TNF-α and IL-6. Indeed, IL-1, IL-6, and TNF-α increase the osteoclasts response to RANKL and consequently osteolysis (Table 1). Estrogen withdrawal after menopause has the same stimulating effect, increasing osteoclastic activity through IL-1, IL-6, and TNF-α effects.18 Proinflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-17 (Table 1) are also elevated in patients with rheumatoid arthritis, contributing to increased RANKL expression and subsequent osteolysis.19 Schett et al have reviewed the important relation between autoimmunity and joint erosion in rheumatoid arthritis, revealing the presence of anti-citrullinated protein antibodies and anti-carbamylated protein antibodies in serum of the patients with rheumatoid arthritis. Molecular interaction between anti-citrullinated protein antibodies and the surface of osteoclast precursor cells via citrullinated vimentin induces differentiation and production of bone-resorbing osteoclasts, resulting in excessive bone resorption.20 Vitamin D3, prostaglandin E2, parathyroid hormone, in addition to IL-1, IL-6, IL-11, and TNF-α, can also induce RANKL expression, leading to excessive osteoclastogenesis (Figure 2).21 Activated T-cells were also reported to regulate bone loss and activation of osteoclastogenesis in vitro through RANKL.22 Contrariwise, TNF-stimulated gene 6 protein is an inflammation-induced protein that can inhibit osteoblastogenesis and osteoclast activation.23 In addition, immunoreceptor tyrosine-based activation motif (ITAM) pathway may contribute to the relationship between immune system and bone as a co-stimulatory pathway in osteoclasts. ITAM-dependent receptors regulate myeloid-derived cells functions. Furthermore, ITAM-containing adapter proteins such as DNAX activation protein-12 and the Fc epsilon receptor I gamma chain (FCER1G) play an essential role in osteoclast differentiation. Suppression of calcineurin–nuclear factor of activated T-cells signaling can reduce the activity of ITAM pathway in the late stage of osteoclast differentiation, leading to the reduction of osteoclast differentiation and activity.24,25 Calcium signaling induces the calmodulin-dependent kinase pathway role in osteoclast formation and plays a crucial role in the autoamplification of the transcription factor nuclear factor of activated T-cells cytoplasmic-1. Further, activation of TRAF6 and c-Fos pathways by RANKL leads to autoamplification of nuclear factor of activated T-cells cytoplasmic-1 and enhances osteoclastogenesis.21

Bottom Line: Paget's disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation.The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders.As a potential osteoimmunological disorder, the treatment of Paget's disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition.

View Article: PubMed Central - PubMed

Affiliation: CHU de Québec Research Centre, CHU de Québec-Université Laval, Quebec City, QC, Canada ; Division of Rheumatology, Department of Medicine, CHU de Québec-Université Laval, Quebec City, QC, Canada.

ABSTRACT
Osteoimmunology represents a large area of research resulting from the cross talk between bone and immune systems. Many cytokines and signaling cascades are involved in the field of osteoimmunology, originating from various cell types. The RANK/receptor activator of nuclear factor Kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling has a pivotal role in osteoimmunology, in addition to proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17. Clinically, osteoimmunological disorders, such as rheumatoid arthritis, osteoporosis, and periodontitis, should be classified according to their pattern of osteoimmunological serum biomarkers. Paget's disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation. With the exception of the cellular responses to measles virus nucleocapsid protein and the interferon-gamma signature, the exact role of the immune system in Paget's disease of bone is not well understood. The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders. As a potential osteoimmunological disorder, the treatment of Paget's disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition.

No MeSH data available.


Related in: MedlinePlus