RESUMEN
Nucleic acid (NA) sensing receptors were first described in the context of host defense. We now know that some endosomal NA sensors play a critical role in the development of systemic autoimmune diseases such as systemic lupus erythematosus, whereas cytosolic Cyclic GMP-AMP Synthase/Stimulator of IFN Genes (cGAS/STING) DNA-detecting pathway has been associated with monogenic autoinflammatory interferonopathies such as Aicardi-Goutieres and Education; collaboration; communication STING-associated vasculopathy with onset in infancy (SAVI). DNaseII hypomorphic patients and DNase-/- IFNaR-/- (double knockout [DKO]) mice also develop an autoinflammatory syndrome associated with an interferon signature. We now add to the description of an unusual clinical manifestation of DKO mice that involves the accrual of trabecular bone in long bone marrow and the formation of ectopic bone within the spleen. This aberrant bone formation is lost not only in STING-deficient but also in Unc93b1-deficient mice and, therefore, depends on the interplay of cells expressing cytosolic and endosomal NA sensing receptors.
Asunto(s)
Endodesoxirribonucleasas/deficiencia , Inflamación/etiología , Interferones/genética , Ácidos Nucleicos/metabolismo , Osteogénesis , Transducción de Señal , Receptores Toll-Like/metabolismo , Animales , Endodesoxirribonucleasas/genética , Femenino , Interferones/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Noqueados , Receptores Toll-Like/genéticaRESUMEN
OBJECTIVE: Inflammation in the bone microenvironment stimulates osteoclast differentiation, resulting in uncoupling of resorption and formation. Mechanisms contributing to the inhibition of osteoblast function in inflammatory diseases, however, have not been elucidated. Rheumatoid arthritis (RA) is a prototype of an inflammatory arthritis that results in focal loss of articular bone. The paucity of bone repair in inflammatory diseases such as RA raises compelling questions regarding the impact of inflammation on bone formation. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity. METHODS: We characterized an innovative variant of a murine model of arthritis in which inflammation is induced in C57BL/6J mice by transfer of arthritogenic K/BxN serum and allowed to resolve. RESULTS: In the setting of resolving inflammation, bone resorption ceased and appositional osteoblast-mediated bone formation was induced, resulting in repair of eroded bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/ß-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled induction of the anabolic and pro-matrix mineralization factors Wnt10b and DKK2, demonstrating the role of inflammation in regulating Wnt signaling. CONCLUSION: Repair of articular bone erosion occurs in the setting of resolving inflammation, accompanied by alterations in the Wnt signaling pathway. These data imply that in inflammatory diseases that result in persistent articular bone loss, strict control of inflammation may not be achieved and may be essential for the generation of an anabolic microenvironment that supports bone formation and repair.
Asunto(s)
Artritis Experimental/metabolismo , Inflamación/metabolismo , Osteoblastos/metabolismo , Osteogénesis/fisiología , Proteínas Wnt/biosíntesis , Vía de Señalización Wnt , Fosfatasa Ácida/metabolismo , Animales , Artritis Experimental/inmunología , Artritis Experimental/patología , Regeneración Ósea/fisiología , Proteínas Relacionadas con la Folistatina/metabolismo , Inflamación/patología , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Isoenzimas/metabolismo , Articulaciones/metabolismo , Articulaciones/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Osteoblastos/patología , Osteoclastos/metabolismo , Osteoclastos/patología , Fosfatasa Ácida TartratorresistenteRESUMEN
In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of articular bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new bone is uncommon in RA, suggesting that bone formation may be compromised at these sites. Dynamic bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic bone. Bone formation rates at bone surfaces adjacent to inflammation were similar to those observed in nonarthritic bone; therefore, osteoblast activity is unlikely to compensate for the increased bone resorption at these sites. Within arthritic bone, the extent of actively mineralizing surface was reduced at bone surfaces adjacent to inflammation compared with bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized bone formation, there was a notable paucity of cells expressing the mid- to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled-related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic bone. Together, these data indicate that the presence of inflammation within arthritic bone impairs osteoblast capacity to form adequate mineralized bone, thus contributing to the net loss of bone and failure of bone repair at sites of focal bone erosion in RA.