Summary
Tumor necrosis factor receptor (TNFR)‐associated factor 6 (TRAF6) is an adapter protein that mediates a wide array of protein–protein interactions via its TRAF domain and a RING finger domain ...that possesses non‐conventional E3 ubiquitin ligase activity. First identified nearly two decades ago as a mediator of interleukin‐1 receptor (IL‐1R)‐mediated activation of NFκB, TRAF6 has since been identified as an actor downstream of multiple receptor families with immunoregulatory functions, including members of the TNFR superfamily, the Toll‐like receptor (TLR) family, tumor growth factor‐β receptors (TGFβR), and T‐cell receptor (TCR). In addition to NFκB, TRAF6 may also direct activation of mitogen‐activated protein kinase (MAPK), phosphoinositide 3‐kinase (PI3K), and interferon regulatory factor pathways. In the context of the immune system, TRAF6‐mediated signals have proven critical for the development, homeostasis, and/or activation of B cells, T cells, and myeloid cells, including macrophages, dendritic cells, and osteoclasts, as well as for organogenesis of thymic and secondary lymphoid tissues. In multiple cellular contexts, TRAF6 function is essential not only for proper activation of the immune system but also for maintaining immune tolerance, and more recent work has begun to identify mechanisms of contextual specificity for TRAF6, involving both regulatory protein interactions, and messenger RNA regulation by microRNAs.
The receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK-osteoprotegerin (OPG) system is critical to bone homeostasis, but genetically deficient mouse models have revealed important roles ...in the immune system as well. RANKL-RANK-OPG is particularly important to T cell biology because of its organogenic control of thymic development and secondary lymphoid tissues influence central T cell tolerance and peripheral T cell function. RANKL-RANK-OPG cytokine-receptor interactions are often controlled by regulation of expression of RANKL on developing T cells, which interacts with RANK expressed on some lymphoid tissue cells to stimulate key downstream signaling pathways that affect critical tuning functions of the T cell compartment, like cell survival and antigen presentation. Activation of peripheral T cells is regulated by RANKL-enhanced dendritic cell survival, and dysregulation of the RANKL-RANK-OPG system in this context is associated with loss of T cell tolerance and autoimmune disease. Given its broader implications for immune homeostasis and osteoimmunology, it is critical to further understand how the RANKL-RANK-OPG system operates in T cell biology.
Bone and the immune system are both complex tissues that respectively regulate the skeleton and the body’s response to invading pathogens. It has now become clear that these organ systems often ...interact in their function. This is particularly true for the development of immune cells in the bone marrow and for the function of bone cells in health and disease. Because these two disciplines developed independently, investigators in each don’t always fully appreciate the significance that the other system has on the function of the tissue they are studying. This review is meant to provide a broad overview of the many ways that bone and immune cells interact so that a better understanding of the role that each plays in the development and function of the other can develop. It is hoped that an appreciation of the interactions of these two organ systems will lead to better therapeutics for diseases that affect either or both.
Selenoproteins containing selenium in the form of selenocysteine are critical for bone remodeling. However, their underlying mechanism of action is not fully understood. Herein, we report the ...identification of selenoprotein W (SELENOW) through large-scale mRNA profiling of receptor activator of nuclear factor (NF)-κΒ ligand (RANKL)-induced osteoclast differentiation, as a protein that is downregulated via RANKL/RANK/tumour necrosis factor receptor-associated factor 6/p38 signaling. RNA-sequencing analysis revealed that SELENOW regulates osteoclastogenic genes. SELENOW overexpression enhances osteoclastogenesis in vitro via nuclear translocation of NF-κB and nuclear factor of activated T-cells cytoplasmic 1 mediated by 14-3-3γ, whereas its deficiency suppresses osteoclast formation. SELENOW-deficient and SELENOW-overexpressing mice exhibit high bone mass phenotype and osteoporosis, respectively. Ectopic SELENOW expression stimulates cell-cell fusion critical for osteoclast maturation as well as bone resorption. Thus, RANKL-dependent repression of SELENOW regulates osteoclast differentiation and blocks osteoporosis caused by overactive osteoclasts. These findings demonstrate a biological link between selenium and bone metabolism.
Osteoclasts are the principal cells that efficiently resorb bone. Numerous studies have attempted to reveal the molecular pathways leading to the differentiation and activation of osteoclasts to ...improve the treatment and prevention of osteoporosis and other bone-destructive diseases. While the cumulative knowledge of osteoclast regulatory molecules, such as receptor activator of nuclear factor-kB ligand (RANKL) and nuclear factor of activated T cells 1 (NFATc1), contributes to the understanding of the developmental progression of osteoclasts, little is known about how the discrete steps of osteoclastogenesis modify osteoclast status but not the absolute number of osteoclasts. The regulatory mechanisms involved in osteoclast maturation but not those involved in differentiation deserve special attention due to their potential use in establishing a more effective treatment strategy: targeting late-phase differentiation while preserving coupled bone formation. Recent studies have shed light on the molecules that govern late-phase osteoclast differentiation and maturation, as well as the metabolic changes needed to adapt to shifting metabolic demands. This review outlines the current understanding of the regulation of osteoclast differentiation, as well as osteoclast metabolic adaptation as a differentiation control mechanism. Additionally, this review introduces molecules that regulate the late-phase osteoclast differentiation and thus minimally impact coupled bone formation.
Highly dense and highly crystalline vanadium dioxide (VO2) thermochromic thin films were successfully sputter-deposited on glass substrates at a low substrate temperature of 300°C. By superimposition ...of RF and DC magnetron sputtering, we were able to fabricate VO2 films with high solar transition efficiency (△Tsol) of 12.8% at a substrate temperature of 300°C, which was comparable to the results attained at 450°C by conventional DC sputtering. The VO2 crystallization at a lower temperature of 300°C could be achieved using a high-energy and high-density plasma induced by RF-superimposed DC sputtering. The hysteresis curves of transmittance as a function of temperature revealed that the VO2 films by RF-superimposed DC sputtered at 300°C exhibited a reduced transition temperature of 59°C and a narrow hysteresis width of 3°C. The enhanced transition properties might result from the compressive stress in the b and c axes as well as the densification of the films due to ion bombardment effect.
•Vanadium dioxide (VO2) films are formed on glass at 300°C by RF+DC sputtering.•The VO2 films deposited at 300°C show good thermochromic properties (△Tsol~13%).•300°C-deposited VO2 shows a lowered Tc of 59°C and a narrow hysteresis width of 3°C.•Tc and hysteresis width are affected by compressive stress and film densification.
Protocadherin-7 (Pcdh7) is a member of the non-clustered protocadherin δ1 subgroup of the cadherin superfamily. Although the cell-intrinsic role of Pcdh7 in osteoclast differentiation has been ...demonstrated, the molecular mechanisms of Pcdh7 regulating osteoclast differentiation remain to be determined. Here, we demonstrate that Pcdh7 contributes to osteoclast differentiation by regulating small GTPases, RhoA and Rac1, through its SET oncoprotein binding domain. Pcdh7 is associated with SET along with RhoA and Rac1 during osteoclast differentiation. Pcdh7-deficient (Pcdh7
) cells showed abolished RANKL-induced RhoA and Rac1 activation, and impaired osteoclast differentiation. Impaired osteoclast differentiation in Pcdh7
cells was restored by retroviral transduction of full-length Pcdh7 but not by a Pcdh7 mutant that lacks SET binding domain. The direct crosslink of the Pcdh7 intracellular region induced the activation of RhoA and Rac1, which was not observed when Pcdh7 lacks the SET binding domain. Additionally, retroviral transduction of the constitutively active form of RhoA and Rac1 completely restored the impaired osteoclast differentiation in Pcdh7
cells. Collectively, these results demonstrate that Pcdh7 controls osteoclast differentiation by regulating RhoA and Rac1 activation through the SET binding domain.
The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of ...mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor α (ERα) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(-) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-κB-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR⁻/⁻ phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.
The mechanisms that regulate the T(H)9 subset of helper T cells and diseases mediated by T(H)9 cells remain poorly defined. Here we found that the costimulatory receptor OX40 was a powerful inducer ...of T(H)9 cells in vitro and T(H)9 cell-dependent airway inflammation in vivo. In polarizing conditions based on transforming growth factor-beta (TGF-beta), ligation of OX40 inhibited the production of induced regulatory T cells and the T(H)17 subset of helper T cells and diverted CD4(+)Foxp3(-) T cells to a T(H)9 phenotype. Mechanistically, OX40 activated the ubiquitin ligase TRAF6, which triggered induction of the kinase NIK in CD4(+) T cells and the noncanonical transcription factor NF-κB pathway; this subsequently led to the generation of T(H)9 cells. Thus, our study identifies a previously unknown mechanism for the induction of T(H)9 cells and may have important clinical implications in allergic inflammation.
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