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I sincerely thank the authors for their contributions to this Special Issue and believe that these notions would help to further our understanding of molecular and cellular mechanisms of bone and cartilage biology, as well as contribute to the development of therapeutic strategies for bone and cartilage diseases. Recent technical and conceptual advances in molecular and cellular biology have dramatically advanced bone and cartilage biology. This Special Issue aims to provide novel notions for skeletal development, and bone and cartilage diseases. This progress has also improved our understanding of the molecular pathogenesis of bone and cartilage diseases, including osteoporosis, osteoarthritis, and rheumatoid arthritis. [Extracted from the article]

Proinflammatory cytokines play critical roles in the pathogenesis of joint diseases. Using a mass spectrometry–based cloning approach, we identified Semaphorin 4D (Sema4D) as an inflammatory cytokine that directly promoted cartilage destruction. Sema4d-deficient mice showed less cartilage destruction than wild-type mice in a model of rheumatoid arthritis. Sema4D induced a proinflammatory response in mouse articular chondrocytes characterized by the induction of proteolytic enzymes that degrade cartilage, such as matrix metalloproteinases (MMPs) and aggrecanases. The activation of Mmp13 and Mmp3 expression in articular chondrocytes by Sema4D did not depend on RhoA, a GTPase that mediates Sema4D-induced cytoskeletal rearrangements. Instead, it required NF-κB signaling and Ras-MEK-Erk1/2 signaling downstream of the receptors Plexin-B2 and c-Met and depended on the transcription factors IκBζ and C/EBPδ. Genetic and pharmacological blockade of these Sema4D signaling pathways inhibited MMP induction in chondrocytes and cartilage destruction in femoral head organ culture. Our results reveal a mechanism by which Sema4D signaling promotes cartilage destruction. Sema4D as cartilage destroyer: Various classical proinflammatory cytokines contribute to cartilage destruction in joint diseases. Murakami et al. found that Semaphorin 4D (Sema4D) was released by inflamed macrophages and stimulated cartilage begin{bmatrix} degradation in articular chondrocytes and cartilage explants. In a mouse model of inflammatory arthritis, Sema4D was increased in synovial fluid, and loss of Sema4D protected against cartilage degeneration. Sema4D elicited these effects by stimulating the expression of transcripts encoding begin{bmatrix}-degrading enzymes downstream of the receptors Plexin-B2 and c-Met and intracellular signaling pathways distinct from those by which Sema4D regulates cell morphology and motility. These findings identify Sema4D as a proinflammatory cytokine in joints and contribute to a broader understanding of the factors that drive joint degeneration. [ABSTRACT FROM AUTHOR]

Introduction Chondrogenesis is an important biological event in endochondral bone development, skeletogenesis, and tissue patterning (1), (2). After condensation of chondrogenic mesenchymal cells, they begin to differentiate into chondrocytes (3). [...], The Sox9 transcription factor plays an essential role in promoting chondrogenesis and regulating expression of chondrocyte extracellular-matrix genes. To identify genes that interact with Sox9 in promoting chondrocyte differentiation, we screened a cDNA library generated from the murine chondrogenic ATDC5 cell line to identify activators of the collagen, type II, α 1 (Col2a1) promoter. Here we have shown that paraspeckle regulatory protein 54-kDa nuclear RNA-binding protein ([p54.sup.nrb]) is an essential link between Sox9-regulated transcription and maturation of Sox9-target gene mRNA. We found that [p54.sup.nrb] physically interacted with Sox9 and enhanced Sox9-dependent transcriptional activation of the Col2a1 promoter. In ATDC5 cells, [p54.sup.nrb] colocalized with Sox9 protein in nuclear paraspeckle bodies, and knockdown of [p54.sup.nrb] suppressed Sox9-dependent Col2a1 expression and promoter activity. We generated a [p54.sup.nrb] mutant construct lacking RNA recognition motifs, and overexpression of mutant [p54.sup.nrb] in ATDC5 cells markedly altered the appearance of paraspeckle bodies and inhibited the maturation of Col2a1 mRNA. The mutant [p54.sup.nrb] inhibited chondrocyte differentiation of mesenchymal cells and mouse metatarsal explants. Furthermore, transgenic mice expressing the mutant [p54.sup.nrb] in the chondrocyte lineage exhibited dwarfism associated with impairment of chondrogenesis. These data suggest that [p54.sup.nrb] plays an important role in the regulation of Sox9 function and the formation of paraspeckle bodies during chondrogenesis.

Hyaluronan (HA) is a major extracellular matrix component whose tissue levels are dynamically regulated during embryonic development. Although the synthesis of HA has been shown to exert a substantial influence on embryonic morphogenesis, the functional importance of the catabolic aspect of HA turnover is poorly understood. Here, we demonstrate that the transmembrane hyaluronidase TMEM2 plays an essential role in neural crest development and the morphogenesis of neural crest derivatives, as evidenced by the presence of severe craniofacial abnormalities in Wnt1-Cre–mediated Tmem2 knockout (Tmem2CKO) mice. Neural crest cells (NCCs) are a migratory population of cells that gives rise to diverse cell lineages, including the craniofacial complex, the peripheral nervous system, and part of the heart. Analysis of Tmem2 expression during NCC formation and migration reveals that Tmem2 is expressed at the site of NCC delamination and in emigrating Sox9-positive NCCs. In Tmem2CKO embryos, the number of NCCs emigrating from the neural tube is greatly reduced. Furthermore, linage tracing reveals that the number of NCCs traversing the ventral migration pathway and the number of post-migratory neural crest derivatives are both significantly reduced in a Tmem2CKO background. In vitro studies using Tmem2-depleted mouse O9-1 neural crest cells demonstrate that Tmem2 expression is essential for the ability of these cells to form focal adhesions on and to migrate into HA-containing substrates. Additionally, we show that Tmem2-deficient NCCs exhibit increased apoptotic cell death in NCC-derived tissues, an observation that is corroborated by in vitro experiments using O9-1 cells. Collectively, our data demonstrate that TMEM2-mediated HA degradation plays an essential role in normal neural crest development. This study reveals the hitherto unrecognized functional importance of HA degradation in embryonic development and highlights the pivotal role of Tmem2 in the developmental process. Author summary: As a major component of the extracellular matrix, hyaluronan is particularly abundant in the extracellular matrix of embryonic tissues, where its expression is dynamically regulated during tissue morphogenetic processes. Tissue levels of hyaluronan are regulated not only by its synthesis but also by its degradation. Curiously, mice lacking known hyaluronidase molecules, including HYAL1 and HYAL2, exhibit minimal embryonic phenotypes. As a result, our understanding of the role of the catabolic aspect of hyaluronan metabolism in embryonic development is quite limited. Here, we show that TMEM2, a recently identified hyaluronidase that degrades hyaluronan on the cell surface, plays a critical role in the development of neural crest cells and their derivatives. Our analyses of Tmem2 conditional knockout mice, Tmem2 knock-in reporter mice, and in vitro cell cultures demonstrate that TMEM2 is essential for generating a tissue environment needed for efficient migration of neural crest cells from the neural tube. Our paper reveals for the first time that the degradation of hyaluronan plays a specific regulatory role in embryonic morphogenesis, and that dysregulation of hyaluronan degradation leads to severe developmental defects. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome has important roles in the pathogenesis of various inflammatory diseases. However, the regulatory mechanisms of the NLRP3 inflammasome are not fully understood. In this study, we attempted to identify molecules that interact with NLRP3 upon its activation. We identified G protein subunit β 1 (GNB1), a downstream molecule of G protein-coupled receptors (GPCRs), which regulates the NLRP3 inflammasome activation. GNB1 was physically associated with NLRP3 via the pyrin domain of NLRP3. Activation of the NLRP3 inflammasome was enhanced in GNB1-knockdown or GNB1-deficient murine macrophages, although a lack of GNB1 did not affect activation of the AIM2 inflammasome. ASC oligomerization induced by NLRP3 was enhanced by GNB1 deficiency. Conversely, NLRP3-dependent ASC oligomerization was inhibited by the overexpression of GNB1. This study indicates that GNB1 negatively regulates NLRP3 inflammasome activation by suppressing NLRP3-dependent ASC oligomerization, and it provides a regulatory mechanism of the NLRP3 inflammasome. The Journal of Immunology, 2019, 202: 1942-1947. [ABSTRACT FROM AUTHOR]