Explore the vast range of titles available.

Bone metastasis involves tumor-induced osteoclast activation, resulting in skeletal tumor progression as well as skeletal disorders. Aberrant expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for osteoclast differentiation, induced by the metastatic tumor cells is responsible for the pathological bone resorption in bone metastasis. A fully human anti-RANKL neutralizing antibody has been developed to block osteoclast activation and is now used for the treatment of patients with bone metastasis and multiple myeloma. On the other hand, numerous studies have revealed that the RANKL/RANK system also contributes to primary tumorigenesis as well as metastasis through osteoclast-independent processes. Furthermore, emerging clinical and preclinical evidence has suggested anti-tumor immune effects of RANKL blockade when added to immune checkpoint inhibitor therapies. Study on the pleiotropic functions of RANKL in tumorigenesis and metastasis is now expanding beyond the bone field and has been established as one of the most important areas of “RANKL biology”.

Bone functions not only as a critical element of the musculoskeletal system but also serves as the primary lymphoid organ harboring hematopoietic stem cells (HSCs) and immune progenitor cells. The interdisciplinary field of osteoimmunology has illuminated the dynamic interactions between the skeletal and immune systems, vital for the maintenance of skeletal tissue homeostasis and the pathogenesis of immune and skeletal diseases. Aberrant immune activation stimulates bone cells such as osteoclasts and osteoblasts, disturbing the bone remodeling and leading to skeletal disorders as seen in autoimmune diseases like rheumatoid arthritis. On the other hand, intricate multicellular network within the bone marrow creates a specialized microenvironment essential for the maintenance and differentiation of HSCs and the progeny. Dysregulation of immune–bone crosstalk in the bone marrow environment can trigger tumorigenesis and exacerbated inflammation. A comprehensive deciphering of the complex “immune–bone crosstalk” leads to a deeper understanding of the pathogenesis of immune diseases as well as skeletal diseases, and might provide insight into potential therapeutic approaches.

Immune responses are crucial not only for host defence against pathogens but also for tissue maintenance and repair after injury. Lymphocytes are involved in the healing process after tissue injury, including bone fracture and muscle damage. However, the specific immune cell subsets and mediators of healing are not entirely clear. Here we show that γδ T cells produce IL-17A, which promotes bone formation and facilitates bone fracture healing. Repair is impaired in IL-17A-deficient mice due to a defect in osteoblastic bone formation. IL-17A accelerates bone formation by stimulating the proliferation and osteoblastic differentiation of mesenchymal progenitor cells. This study identifies a novel role for IL-17-producing γδ T cells in skeletal tissue regeneration. γδ T cells are innate-like lymphocytes that regulate immune responses by producing IL-17A or IFN-γ, but have no known role in bone healing. Here the authors show a nonimmune bone-regenerative function of IL-17A produced by the Vγ6+ subset in mice.

The immune system evolved to efficiently eradicate invading bacteria and terminate inflammation through balancing inflammatory and regulatory T-cell responses. In autoimmune arthritis, pathogenic T H 17 cells induce bone destruction and autoimmune inflammation. However, whether a beneficial function of T-cell-induced bone damage exists is unclear. Here, we show that bone-damaging T cells have a critical function in the eradication of bacteria in a mouse model of periodontitis, which is the most common infectious disease. Bacterial invasion leads to the generation of specialized T H 17 cells that protect against bacteria by evoking mucosal immune responses as well as inducing bone damage, the latter of which also inhibits infection by removing the tooth. Thus, bone-damaging T cells, which may have developed to stop local infection by inducing tooth loss, function as a double-edged sword by protecting against pathogens while also inducing skeletal tissue degradation. IL-17-producing T cells are protective against infection, but the authors of this article previously showed that these cells also contribute to inflammatory bone destruction. Here they show in the context of periodontitis that microbiota-driven Th17-mediated bone destruction may actually be a physiological rather than a pathological process, as associated tooth loss prevents dissemination of oral bacteria.

Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases including autoimmune arthritis, cancer and inflammatory colitis. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Here, we identify ETS1 as the key transcription factor governing the pathological tissue-remodeling programs in fibroblasts. In arthritis, ETS1 drives polarization toward tissue-destructive fibroblasts by orchestrating hitherto undescribed regulatory elements of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL) as well as matrix metalloproteinases. Fibroblast-specific ETS1 deletion resulted in ameliorated bone and cartilage damage under arthritic conditions without affecting the inflammation level. Cross-tissue fibroblast single-cell data analyses and genetic loss-of-function experiments lent support to the notion that ETS1 defines the perturbation-specific fibroblasts shared among various disease settings. These findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications.Osteoclastic bone destruction is mediated by factors such as RANKL elaborated by tissue-destructive fibroblasts. Takayanagi and colleagues identify the transcription factor Ets1 as a major regulator of these pathogenic cells.

The ontogeny and fate of stem cells have been extensively investigated by lineage-tracing approaches. At distinct anatomical sites, bone tissue harbors multiple types of skeletal stem cells, which may independently supply osteogenic cells in a site-specific manner. Periosteal stem cells (PSCs) and growth plate resting zone stem cells (RZSCs) critically contribute to intramembranous and endochondral bone formation, respectively. However, it remains unclear whether there is functional crosstalk between these two types of skeletal stem cells. Here we show PSCs are not only required for intramembranous bone formation, but also for the growth plate maintenance and prolonged longitudinal bone growth. Mice deficient in PSCs display progressive defects in intramembranous and endochondral bone formation, the latter of which is caused by a deficiency in PSC-derived Indian hedgehog (Ihh). PSC-specific deletion of Ihh impairs the maintenance of the RZSCs, leading to a severe defect in endochondral bone formation in postnatal life. Thus, crosstalk between periosteal and growth plate stem cells is essential for post-developmental skeletal growth. Intramembranous and endochondral bone formation have been considered to be independent processes mediated by independent stem cells. Here the authors show that periosteal stem cells participate in both types of bone formation, supporting endochondral formation by producing Ihh.

The methylation of arginine residues in proteins is a post-translational modification that contributes to a wide range of biological processes. Many cytokines involved in T cell development and activation utilize the common cytokine receptor γ-chain (γc) and the kinase JAK3 for signal transduction, but the regulatory mechanism that underlies the expression of these factors remains unclear. Here we found that the arginine methyltransferase PRMT5 was essential for the maintenance of invariant natural killer T cells (iNKT cells), CD4 + T cells and CD8 + T cells. T cell–specific deletion of Prmt5 led to a marked reduction in signaling via γc-family cytokines and a substantial loss of thymic iNKT cells, as well as a decreased number of peripheral CD4 + T cells and CD8 + T cells. PRMT5 induced the symmetric dimethylation of Sm proteins that promoted the splicing of pre-mRNA encoding γc and JAK3, and this critically contributed to the expression of γc and JAK3. Thus, arginine methylation regulates strength of signaling via γc-family cytokines by facilitating the expression of signal-transducing components. PRMT arginine methyltransferases mediate post-translational modification. Takayanagi and colleagues show that a lack of PRMT5 in cells of the T cell lineage compromises their response to cytokines dependent on the common γ-chain, due to aberrant splicing of mRNA transcripts encoding the common γ-chain and its associated kinase JAK3.

Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss. However, it has been poorly understood whether ICs regulate bone metabolism directly. Here we show that the level of osteoclastogenesis is determined by the strength of FcRγ signalling, which is dependent on the relative expression of positive and negative FcγRs (FcγRI/III/IV and IIB, respectively) as well as the availability of their ligands, ICs. Under physiological conditions, unexpectedly, FcγRIII inhibits osteoclastogenesis by depriving other osteoclastogenic Ig-like receptors of FcRγ. Fcgr2b −/− mice lose bone upon the onset of a hypergammaglobulinemia or the administration of IgG1 ICs, which act mainly through FcγRIII. The IgG2 IC activates osteoclastogenesis by binding to FcγRI and FcγRIV, which is induced under inflammatory conditions. These results demonstrate a link between the adaptive immunity and bone, suggesting a regulatory role for ICs in bone resorption in general, and not only in inflammatory diseases. Bone and the immune system are functionally intertwined. This study shows that osteoclastogenesis is modulated by the intensity of Fcγ receptor signalling, which is shaped by the balance between the positive and negative Fcγ receptors expressed on osteoclasts and the availability of their ligands, immune complexes.

Here, we reported particles with approximately 80-μm diameter with phase-separated morphology of ternary polymer blends containing poly(4-butyltriphenylamine) (PBTPA), poly(methyl methacrylate) (PMMA), and PBTPA-b-PMMA fabricated via a microfluidic emulsification technique with a Y-shaped microreactor followed by a solvent evaporation. Addition of block copolymer changed the macroscopic structure from core-shell to Janus and more complicated sea-island type with the increase of the block copolymer content. The Janus structure with a PMMA hemisphere containing small PBTPA domain was observed at 10 wt% of the block copolymer. Meanwhile, the rapid evaporation changed the morphology macroscopically from the Janus to the undeveloped one where PMMA-rich phase mainly located at center sandwiched with outside PBTPA phases, suggesting that morphologies are governed by the kinetical factors together with the conventionally accepted thermodynamic ones. After the solvent annealing with toluene, distinct and enlarged PMMA phase appeared radiately, of which size gradiently decreased from the surface to the center (200–500 nm) in each particle.

Immunological self-tolerance is established in the thymus by the expression of virtually all self-antigens, including tissue-restricted antigens (TRAs) and cell-type-restricted antigens (CRAs). Despite a wealth of knowledge about the transcriptional regulation of TRA genes, posttranscriptional regulation remains poorly understood. Here, we show that protein arginine methylation plays an essential role in central immune tolerance by maximizing the self-antigen repertoire in medullary thymic epithelial cells (mTECs). Protein arginine methyltransferase-5 (Prmt5) was required for pre-mRNA splicing of certain key genes in tolerance induction, including Aire as well as various genes encoding TRAs. Mice lacking Prmt5 specifically in thymic epithelial cells exhibited an altered thymic T cell selection, leading to the breakdown of immune tolerance accompanied by both autoimmune responses and enhanced antitumor immunity. Thus, arginine methylation and transcript splicing are essential for establishing immune tolerance and may serve as a therapeutic target in autoimmune diseases as well as cancer immunotherapy.