Inflammatory diseases decrease the extracellular environmental pH. However, whether proton-activated G protein-coupled receptors (GPCRs) can regulate the development of osteoarthritis (OA) is largely ...unknown. In this study, we report that proton-activated GPR4 is essential for OA development. We found a marked increase in expression of the proton-activated GPR4 in human and mouse OA cartilage. Lentivirus-mediated overexpression of GPR4 in mouse joints accelerated the development of OA, including promotion of articular cartilage damage, synovial hyperplasia, and osteophyte formation, while Gpr4 knockout effectively attenuated the development of posttraumatic and aging-associated OA in mice. We also found that inhibition of GPR4 with the antagonist NE52-QQ57 ameliorated OA progression in mice, promoted extracellular matrix (ECM) production, and protected cartilage from degradation in human articular cartilage explants. Moreover, GPR4 overexpression upregulated matrix-degrading enzymes' expression and inflammation factors under pro-inflammatory and slightly acidic conditions. Mechanistically, GPR4 suppressed chondrocyte differentiation and upregulated cartilage homeostasis through NF-κB/MAPK signaling activation by regulating CXCR7/CXCL12 expression. Together, our results take the lead to illustrate that proton-activated GPCR acts as a key regulator for OA pathogenesis in vivo, and support that GPR4 could be a promising therapeutic target for OA treatment.
Prostaglandin E2 (PGE2), a major cyclooxygenase-2 (COX-2) product, is highly secreted by the osteoblast lineage in the subchondral bone tissue of osteoarthritis (OA) patients. However, NSAIDs, ...including COX-2 inhibitors, have severe side effects during OA treatment. Therefore, the identification of novel drug targets of PGE2 signaling in OA progression is urgently needed. Osteoclasts play a critical role in subchondral bone homeostasis and OA-related pain. However, the mechanisms by which PGE2 regulates osteoclast function and subsequently subchondral bone homeostasis are largely unknown. Here, we show that PGE2 acts via EP4 receptors on osteoclasts during the progression of OA and OA-related pain. Our data show that while PGE2 mediates migration and osteoclastogenesis via its EP2 and EP4 receptors, tissue-specific knockout of only the EP4 receptor in osteoclasts (EP4
) reduced disease progression and osteophyte formation in a murine model of OA. Furthermore, OA-related pain was alleviated in the EP4
mice, with reduced Netrin-1 secretion and CGRP-positive sensory innervation of the subchondral bone. The expression of platelet-derived growth factor-BB (PDGF-BB) was also lower in the EP4
mice, which resulted in reduced type H blood vessel formation in subchondral bone. Importantly, we identified a novel potent EP4 antagonist, HL-43, which showed in vitro and in vivo effects consistent with those observed in the EP4
mice. Finally, we showed that the Gαs/PI3K/AKT/MAPK signaling pathway is downstream of EP4 activation via PGE2 in osteoclasts. Together, our data demonstrate that PGE2/EP4 signaling in osteoclasts mediates angiogenesis and sensory neuron innervation in subchondral bone, promoting OA progression and pain, and that inhibition of EP4 with HL-43 has therapeutic potential in OA.
Since climatic condition is the important foundation for human subsistence and development and the key factor in sustainable development of economy and society, climate change has been a global issue ...attracting great attentions of politicians, scientists, governments, and the public alike throughout the world. Existing climate regionalization in China aims to characterize the regional differences in climate based on years of the mean value of different climate indexes. However, with the accelerating climate change nowadays, existing climate regionalization cannot represent the regional difference of climate change, nor can it reflect the disasters and environmental risks incurred from climate changes. This paper utilizes the tendency value and fluctuation value of temperature and precipitation from 1961 to 2010 to identify the climate change quantitatively, and completes the climate change regionalization in China (1961–2010) with county administrative regionalization as the unit in combination with China’s terrain feature. Level-I regionalization divides China’s climate change (1961–2010) into five tendency zones based on the tendency of temperature and precipitation, which are respectively Northeast China-North China warm-dry trend zone, East China-Central China wet-warm trend zone, Southwest China-South China dry-warm trend zone, Southeast Tibet-Southwest China wet-warm trend zone, and Northwest China-Qinghai-Tibet Plateau warm-wet trend zone; level-II regionalization refers to fourteen fluctuation regions based on level-I regionalization according to the fluctuation of temperature and precipitation.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Lanzhou Fat-Tail sheep (LFTS, long fat-tailed sheep) is an endangered sheep breed in China with a fat tail compared to the traditional local varieties, Small Tail Han sheep (STHS, thin-tailed ...sheep) with a small tail, and Tibetan sheep (TS, short thin-tailed sheep) with a little tail. However, little is known regarding how tail fat deposition is regulated by long noncoding RNA (lncRNA). To evaluate the lncRNA and mRNA associated with tail fat deposition and development among these breeds, high-throughput RNA sequencing of three individuals each of LFTS, STHS, and TS were performed and analyzed in this study. RNA sequencing data from these three groups revealed 10 differentially expressed genes (DEGs) and 37 differentially expressed lncRNAs between the LFTS and STHS groups, 390 DEGs and 59 differentially expressed lncRNAs between the LFTS and TS groups, and 80 DEGs and 16 differentially expressed lncRNAs between the STHS and TS groups (
-value < 0.05 and fold change ≥ 2), respectively. Gene Ontology and pathway analysis of DEGs and target genes of differentially expressed lncRNAs revealed enrichment in fatty acid metabolism and fatty acid elongation-related pathways that contribute to fat deposition. Subsequently, the expression of 14 DEGs and 6 differentially expressed lncRNAs was validated by quantitative real-time PCR. Finally, two co-expression networks of differentially expressed mRNA and lncRNAs were constructed. The results suggested that some differentially expressed lncRNAs (
, and
) may play crucial roles as core lncRNAs in tail fat deposition processes. In summary, the present study extends the sheep tail fat lncRNA database and these differentially expressed mRNA and lncRNAs may provide novel candidate regulators for future genetic and molecular studies on tail fat deposition of sheep.
The
larval central nervous system comprises the central brain, ventral nerve cord and optic lobe. In these regions, neuroblasts (NBs) divide asymmetrically to self-renew and generate differentiated ...neurons or glia. To date, mechanisms of preventing neuron dedifferentiation are still unclear, especially in the optic lobe. Here, we show that the zinc-finger transcription factor Nerfin-1 is expressed in early-stage medulla neurons and is essential for maintaining their differentiation. Loss of Nerfin-1 activates Notch signaling, which promotes neuron-to-NB reversion. Repressing Notch signaling largely rescues dedifferentiation in
mutant clones. Thus, we conclude that Nerfin-1 represses Notch activity in medulla neurons and prevents them from dedifferentiation.
Understanding the process of replication and transcription of SARS-CoV-2 is essential for antiviral strategy development. The replicase polyprotein is indispensable for viral replication. However, ...whether all nsps derived from the replicase polyprotein of SARS-CoV-2 are indispensable is not fully understood. In this study, we utilized the SARS-CoV-2 replicon as the system to investigate the role of each nsp in viral replication. We found that except for nsp16, all the nsp deletions drastically impair the replication of the replicon, and nsp14 could recover the replication deficiency caused by its deletion in the viral replicon. Due to the unsuccessful expressions of nsp1, nsp3, and nsp16, we could not draw a conclusion about their
in trans
-rescue functions. Our study provided a new angle to understand the role of each nsp in viral replication and transcription, helping the evaluation of nsps as the target for antiviral drug development.
Chromatin remodeling processes are among the most important regulatory mechanisms in controlling cell proliferation and regeneration. Drosophila intestinal stem cells (ISCs) exhibit self-renewal ...potentials, maintain tissue homeostasis, and serve as an excellent model for studying cell growth and regeneration. In this study, we show that Brahma (Brm) chromatin-remodeling complex is required for ISC proliferation and damage-induced midgut regeneration in a lineage-specific manner. ISCs and enteroblasts exhibit high levels of Brm proteins; and without Brm, ISC proliferation and differentiation are impaired. Importantly, the Brm complex participates in ISC proliferation induced by the Scalloped-Yorkie transcriptional complex and that the Hippo (Hpo) signaling pathway directly restricted ISC proliferation by regulating Brm protein levels by inducing caspase-dependent cleavage of Brm. The cleavage resistant form of Brm protein promoted ISC proliferation. Our findings highlighted the importance of Hpo signaling in regulating epigenetic components such as Brm to control downstream transcription and hence ISC proliferation. DOI:http://dx.doi.org/10.7554/eLife.00999.001.
Switching Markov jump linear system (SMJLS), a special hybrid system, has attracted a lot of studies recently. SMJLS is governed by stochastic and deterministic commutations. This paper focuses on ...the switching strategy which stabilizes the SMJLS in a finite time interval in order to further expand the existing results and investigate new aspects of such systems. Several sufficient conditions for finite-time stability of discrete-time SMJLS are provided, and the numerical problems in these sufficient conditions are solved by solving linear matrix inequalities (LMIs). Finally, numerical examples are given to show the feasibility and effectiveness of the results.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
10.
LGR4: A new receptor for a stronger bone Jin, Yunyun; Yang, Yingzi
Science China. Life Sciences/Science China. Life sciences,
07/2016, Volume:
59, Issue:
7
Journal Article
Peer reviewed
Open access
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
