Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Cherubism/genetics , Cherubism/pathology , Infections/immunology , Inflammation/genetics , Macrophages/immunology , Animals , Cherubism/immunology , Disease Models, Animal , Heterozygote , Infections/genetics , Infections/pathology , Inflammation/pathology , Mice , Mice, Knockout , Mutation, MissenseABSTRACT
Autoinflammatory bone disease is a new branch of autoinflammatory diseases caused by seemingly unprovoked activation of the innate immune system leading to an osseous inflammatory process. The inflammatory bone lesions in these disorders are characterized by chronic inflammation that is typically culture negative with no demonstrable organism on histopathology. The most common autoinflammatory bone diseases in childhood include chronic nonbacterial osteomyelitis (CNO), synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, Majeed syndrome, deficiency of interleukin-1 receptor antagonist, and cherubism. In this article, the authors focus on CNO and summarize the distinct genetic autoinflammatory bone syndromes.
Subject(s)
Bone Diseases/immunology , Hereditary Autoinflammatory Diseases/immunology , Acne Vulgaris/diagnosis , Acne Vulgaris/immunology , Acne Vulgaris/therapy , Acquired Hyperostosis Syndrome/diagnosis , Acquired Hyperostosis Syndrome/immunology , Acquired Hyperostosis Syndrome/therapy , Anemia, Dyserythropoietic, Congenital/diagnosis , Anemia, Dyserythropoietic, Congenital/immunology , Anemia, Dyserythropoietic, Congenital/therapy , Bone Diseases/diagnosis , Bone Diseases/therapy , Cherubism/diagnosis , Cherubism/immunology , Cherubism/therapy , Chronic Disease , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/therapy , Humans , Hyperostosis/diagnosis , Hyperostosis/immunology , Hyperostosis/therapy , Immunologic Deficiency Syndromes , Inflammation , Interleukin 1 Receptor Antagonist Protein/immunology , Osteitis/diagnosis , Osteitis/immunology , Osteitis/therapy , Osteomyelitis/diagnosis , Osteomyelitis/immunology , Osteomyelitis/therapy , Syndrome , Synovitis/diagnosis , Synovitis/immunology , Synovitis/therapyABSTRACT
Autoinflammatory bone disorders are characterized by chronic non-infectious osteomyelitis and inflammation-induced bone resorption and result from aberrant activation of the innate immune system. Sporadic chronic non-bacterial osteomyelitis (CNO) is the most common disease subtype. The clinical picture is highly variable and the exact underlying pathophysiology remains to be determined. Recently, novel insights in the pathophysiology of sterile bone inflammation have been gathered by analyzing patients with rare, monogenic inflammatory diseases. In this overview CNO and Majeed syndrome, cherubism, hypophosphatasia and primary hypertrophic osteoarthropathy will be discussed. For the latter four disorders, a genetic cause affecting bone metabolism and leading to chronic bone inflammation has been described. The exact pathophysiology of CNO remains to be determined. Insights from monogenic autoinflammatory bone diseases and the identification of distinct inflammatory pathways may help to understand the pathogenesis of bone inflammation and inflammation-induced bone resorption in more common diseases.
Subject(s)
Bone Diseases/genetics , Bone Diseases/immunology , Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/immunology , Anemia, Dyserythropoietic, Congenital/genetics , Anemia, Dyserythropoietic, Congenital/immunology , Animals , Bone Resorption/genetics , Bone Resorption/immunology , Cherubism/genetics , Cherubism/immunology , Chronic Disease , Genetic Predisposition to Disease , Humans , Hypophosphatasia/genetics , Hypophosphatasia/immunology , Immunologic Deficiency Syndromes , Inflammation/genetics , Inflammation/immunology , Mice , Osteoarthropathy, Primary Hypertrophic/genetics , Osteoarthropathy, Primary Hypertrophic/immunology , Osteomyelitis/genetics , Osteomyelitis/immunology , Rare Diseases/geneticsABSTRACT
Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Cherubism/genetics , Cherubism/physiopathology , Inflammation/immunology , Adaptor Proteins, Signal Transducing/genetics , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/physiopathology , Bone Resorption/genetics , Bone Resorption/immunology , Bone Resorption/physiopathology , Calcineurin/metabolism , Cherubism/immunology , Disease Models, Animal , Germ-Line Mutation , Humans , Inflammation/genetics , Inflammation/physiopathology , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Osteoclasts/immunology , Osteoclasts/metabolism , Phosphorylation , Transcriptional ActivationABSTRACT
PURPOSE OF REVIEW: This review provides an update on clinical, genetic, and immunologic aspects of the autoinflammatory bone disorders. RECENT FINDINGS: Chronic noninfectious inflammation of the bone is a clinical feature of both chronic recurrent multifocal osteomyelitis and (to a lesser degree) cherubism. The genes responsible for Majeed syndrome (LPIN2), murine chronic multifocal osteomyelitis (pstpip2), and cherubism (SH3BP2 and possibly PTPN11) have been identified. Murine models of both chronic recurrent multifocal osteomyelitis and cherubism have demonstrated that the bone inflammation is mediated by hematopoietically derived cells and can occur in the absence of a functioning adaptive immune system. As the immunologic defects become better defined, the cells of the myeloid lineage are emerging as the primary players. SUMMARY: Chronic multifocal osteomyelitis and cherubism are hereditary chronic inflammatory disorders in which bone is the primary inflammatory target. Recent genetic and immunologic discoveries demonstrate involvement of the innate immune system, which places these entities in the category of autoinflammatory disorders.
