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Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. To investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma, we constructed RIG-I knockout, RIG-I-overexpressing B16-F10 and RIG-I knockdown A375 melanoma cell lines, and analyzed the RIG-I-mediated change in the biological behavior of tumor cells in spontaneous and poly (I:C)-induced RIG-I activation. Cell proliferation, cell cycling, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation assay, Annexin V–PI staining assay and Transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently by Ki67 staining and TUNEL assays. Furthermore, Western blotting was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Our data showed that RIG-I promotes apoptosis and inhibits proliferation by G1 phase cell cycle arrest in the melanoma cell lines. Mechanistically, RIG-I induced the phosphorylation of p38 MAPK and MAPK kinases MKK3 and MKK4. In conclusion, the current study demonstrated that RIG-I suppressed the development of melanoma by regulating the activity of the MKK/p38 MAPK signaling pathway, which is relevant to research on novel therapeutic targets for this malignant disease.

The baryonic Tully-Fisher relation (BTFR), which connects the baryonic mass of galaxies with their circular velocities, has been validated across a wide range of galaxies, from dwarf galaxies to massive galaxies. Recent studies have found that several ultra-diffuse galaxies (UDGs) deviate significantly from the BTFR, indicating a galaxy population with abnormal dynamical properties. However, such studies were still confined within a small sample size. In this study, we used the 100% complete Arecibo Legacy Fast Arecibo L-band Feed Array (ALFALFA) to investigate the BTFR of 88 HI-rich UDGs (HUDGs), which is the largest UDG sample with dynamical information. We found that the HUDGs form a continuous distribution in the BTFR diagram, with high-velocity galaxies consistent with normal dwarf galaxies at 1 $\sigma$ level, and low-velocity galaxies deviating from the BTFR, in line with that reported in the literature. We point out that the observed deviation may be subject to various selection effects or systemic biases. Nevertheless, we found that the significance of the deviation of HUDGs from the BTFR and TFR are different, i.e., they either deviate from the BTFR or from the TFR. Our result indicates that a high-gas fraction may play an important role in explaining the deviation of HUDGs from BTFR., Comment: 12 pages, 9 figures, 1 table, accepted for publication in ApJL

NGC 2915 is a unique nearby galaxy that is classified as an isolated blue compact dwarf based on its optical appearance but has an extremely extended H i gas disk with prominent Sd-type spiral arms. To unveil the starburst-triggering mystery of NGC 2915, we performed a comprehensive analysis of deep VLT/MUSE integral field spectroscopic observations that cover the star-forming region in the central kiloparsec of the galaxy. We find that episodes of bursty star formation have recurred in different locations throughout the central region, and the most recent one peaked around 50 Myr ago. The bursty star formation has significantly disturbed the kinematics of the ionized gas but not the neutral atomic gas, which implies that the two gas phases are largely spatially decoupled along the line of sight. No evidence for an active galactic nucleus is found based on the classical line-ratio diagnostic diagrams. The ionized gas metallicities have a positive radial gradient, which confirms the previous study based on several individual H ii regions and may be attributed to both the stellar feedback-driven outflows and metal-poor gas inflow. Evidence for metal-poor gas infall or inflow includes discoveries of high-speed collisions between gas clouds of different metallicities, localized gas metallicity drops and unusually small metallicity differences between gas and stars. The central stellar disk appears to be counter-rotating with respect to the extended H i disk, implying that the recent episodes of bursty star formation have been sustained by externally accreted gas., 14 pages, 16 figures. Accepted for publication in A&A

Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

Adhesion G protein-coupled receptor A1 (ADGRA1, also known as GPR123) belongs to the G protein-coupled receptors (GPCRs) family and is well conserved in the vertebrate lineage. However, the structure of ADGRA1 is unique and its physiological function remains unknown. Previous studies have shown that Adgra1 is predominantly expressed in the central nervous system (CNS), indicating its important role in the transduction of neural signals. The aim of this study is to investigate the central function of Adgra1 in vivo and clarify its physiological significance by establishing an Adgra1-deficient mouse (Adgra1−/−) model. The results show that Adgra1−/− male mice exhibit decreased body weight with normal food intake and locomotion, shrinkage of body mass, increased lipolysis, and hypermetabolic activity. Meanwhile, mutant male mice present elevated core temperature coupled with resistance to hypothermia upon cold stimulus. Further studies show that tyrosine hydroxylase (TH) and β3-adrenergic receptor (β3-AR), indicators of sympathetic nerve excitability, are activated as well as their downstream molecules including uncoupling protein 1 (UCP1), coactivator 1 alpha (PGC1-α) in brown adipose tissue (BAT), and hormone-sensitive lipase (HSL) in white adipose tissue (WAT). In addition, mutant male mice have higher levels of serum T3, T4, accompanied by increased mRNAs of hypothalamus–pituitary–thyroid axis. Finally, Adgra1−/− male mice present abnormal activation of PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus. Overexpression of ADGRA1 in Neuro2A cell line appears to suppress these two signaling pathways. In contrast, Adgra1−/− female mice show comparable body weight along with normal metabolic process to their sex-matched controls. Collectively, ADGRA1 is a negative regulator of sympathetic nervous system (SNS) and hypothalamus–pituitary–thyroid axis by regulating PI3K/AKT/GSK3β and MEK/ERK pathways in hypothalamus of male mice, suggesting an important role of ADGRA1 in maintaining metabolic homeostasis including energy expenditure and thermogenic balance.

Objective To compare the clinical therapeutic effect on epiphora as sequela of peripheral facial paralysis treated with pricking technqiue of fire needling therapy at Chengqi (承泣 ST1) and acupuncture treatment at conventional acupoints. Methods From September 2018 through to October 2018, 64 cases of epiphora as sequela of peripheral facial paralysis were collected from the Department of Acupuncture-Moxibustion in Suzhou TCM Hospital. According to random number table, they were divided into an observation group and a control group, 32 cases in each one. In the observation group, pricking technique of fire needling therapy was used at ST1, once every two days. In the control group, acupuncture with filiform needle was applied to Jīngming (睛明BL1), Taiyang (太阳EX-HN5), Tongzĭliao (瞳子髎GB1), Sibai (四白ST2) and Quanliao (颧髎SI18) on the affected side as well as Hegŭ (合谷LI4) on the contralateral side, once per day. The 10-day treatment was as one 1 course and the consecutive 3 courses of treatment were required in either of the groups. Before and after treatment, Munk grade, clinical effective rate and the number of treatments were observed in the evaluation of therapeutic effect. Results After treatment, Munk grade was improved in the patients of the two groups (both P Conclusion Pricking technique of fire needling therapy at ST1 achieves the better effect on epiphora as sequela of peripheral facial paralysis as compared with acupuncture at conventional acupoints.

Aims: There is a spatially resolved star-forming main sequence (rSFMS) and mass-metallicity relation (rMZR) of galaxies in local universe. We know that the global mass-metallicity relation (MZR) results from the integral of rMZR, and it will evolve with the redshift. However, the evolution of rMZR with redshift is still unclear due to the low spatial resolution and signal-to-noise ratio. There are currently too few observations beyond local universe, and only simulations can reproduce the evolution of rMZR with redshift. Methods: In this work, we select ten emission-line galaxies with an average redshift of $z\sim 0.26$ from MUSE-Wide DR1. We obtain the spatially resolved star formation rate (SFR) and metallicity from the integral field spectroscopy (IFS), as well as the stellar mass surface density from the 3D-HST photometry. We derive the rSFMS and rMZR at $z\sim 0.26$ and compare them with local galaxies. Results: We find the rSFMS of galaxies at $z\sim 0.26$ has a slope of $\sim$0.771. The rMZR exists at $z\sim 0.26$, showing a similar shape to the local universe but a lower average metallicity about $\sim$0.11 dex than the local one. In addition, we also study their spatially resolved fundamental metallicity relation (rFMR). However, there is no obvious evidence that rFMR exists at $z\sim$0.26 and it is not an extension of rMZR at a high SFR. Conclusions: Similar to their global versions, the rSFMS and rMZR of galaxies also evolve with redshift. Given the fixed stellar mass, galaxies at higher redshift show higher SFR and lower metallicity. These suggest that the evolution of the global galaxy properties with redshift may result from integrating the evolution of spatially resolved properties of galaxies., Comment: 9 pages, 8 figures, accepted for publication in A&A

Low-mass compact stellar systems (CSSs; $M_{\star}$ $, 8 pages, 5 figures, published in ApJL

On the β plane approximation, the two-layer quasigeostrophic mode is used to study the baroclinic instability of the quadric shear basic zonal flows on a uniform bottom topography. The phase speed and growth rate of instability waves are functions of the shear zonal basic flows and bottom topographic slope. The study focus is on the effects of topography and the quadric shear basic zonal flows (the second derivative of basic zonal flows is not zero). The meridional slope destabilise (stabilise) zonal flows, it plays an unstable role in disturbance, moreover the effect of the second derivative of basic zonal flows is to accelerate the instability of disturbance. The zonal slope always destabilises the zonal basic flows through zonal and meridional wavenumber. Moreover, the effect of the second derivative of basic zonal flows is to accelerate the instability of disturbance.

Background Serine threonine kinase 10 (STK10) is an ERM kinase involved in the activation of ERM proteins and plays an essential role in the aggregation and adhesion of lymphocytes. STK10 is expressed in about 17 cancer types, including cervical cancer. Cervical cancer is the fourth most common cancer that seriously threatens women’s health worldwide. Previous studies have shown that STK10 may affect LFA-1-mediated cell adhesion. Other studies reported a mutation (R634H) of STK10 detected in peripheral T-cell lymphoma. This study aimed to evaluate the functional roles of STK10 in the pathogenesis of cervical cancer. Methods We generated STK10 knockout cervical cancer cell lines using the CRISPR-Cas9 gene-editing system, and further analyzed the effects of STK10 deficiency on tumor biological behaviors. The proliferation, apoptosis, migration and invasive activity of these cells were respectively detected by BrdU incorporation, AnnexinV/propidium iodide (PI) staining, wound healing assay and Transwell assays without and with Matrigel. The phosphorylation and expression level of indicated proteins were analyzed by Western blot. The differential expression genes between STK10 knockout and control cells were identified by RNA-seq analysis and further confirmed using qRT-PCR. Results Our data revealed that target deletion of STK10 does not affect cell proliferation and apoptosis, but promotes the adhesion, migration, and invasion of cervical cancer cells. Most strikingly, the phosphorylation and expression level of ezrin and other ERM proteins in STK10 knockout cells was comparable with that in the control cells. Further, RNA-seq analysis indicated that the knockout of STK10 resulted in a profound alteration of gene expression in cervical cancer cells. Conclusions This is the first study to provide evidence that STK10 executes various physiological functions in addition to phosphorylation of ERM proteins, and plays a vital role in the migration and invasion of cervical cancer cells.

Testis-specific genes are prone to affect spermatogenesis or sperm fertility, and thus may play pivotal roles in male reproduction. However, whether a gene really affects male reproduction in vivo needs to be confirmed using a gene knock-out (KO) model, a 'gold standard' method. Increasing studies have found that some of the evolutionarily conserved testis-enriched genes are not essential for male fertility. In this study, we report that 1700121C10Rik, a previously uncharacterized gene, is specifically expressed in the testis and produces two long noncoding RNAs (lncRNAs) in mouse: Transcript 1 and Transcript 2. qRT-PCR, northern blotting, and in situ hybridization revealed that expression of both the lncRNAs commenced at the onset of sexual maturity and was predominant in round and elongating spermatids during spermiogenesis. Moreover, we found different subcellular localization of Transcript 1 and Transcript 2 that was predominant in the cytoplasm and nucleus, respectively. 1700121C10Rik-KO mouse model disrupting Transcript 1 and Transcript 2 expression was generated by CRISPR/Cas9 to determine their role in male reproduction. Results showed that 1700121C10Rik-KO male mice were fully fertile with approximately standard testis size, testicular histology, sperm production, sperm morphology, sperm motility, and induction of acrosome reaction. Thus, we conclude that both the testis-specific 1700121C10Rik-produced lncRNAs are dispensable for male fertility in mice under standard laboratory conditions.

Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1−/− mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.

Purpose Tumor drug resistance limits the response to chemotherapy. Interestingly, sequential combination therapy enhances the anticancer efficacy of drugs like cisplatin (CDDP) via synergistic effects. We assayed the synergistic effects of combined photodynamic therapy programmed death receptor-ligand 1 (PDT) and chemotherapy in malignant Hep-2 cells. Methods In the cultured Hep-2 cells, meta-tetra(hydroxyphenyl)chlorin (m-THPC) and CDDP were administered separately or in combination. The cellular viability and apoptosis were assessed, accompanied by measurement of the expression of Bax, Bcl-2, ATG-7, and LC3 (LC3-I and LC3-II). Additionally, nuclear chromatin changes, drug retention, and PD-L1 expression were further investigated following different treatments. Results The sequential treatment significantly diminished cell viability and induced cell apoptosis, in consistency with the usage of single therapeutic strategies, as reflected by an increase in Bax expression and decrease of Bcl-2 expression. Moreover, ATG-7 and LC3-II/LC3-I ratio were reduced after administration of the sequential treatment. Synergetic effect of nuclear chromatin configuration, negative effects of cellular drug retention, and a decrease in PD-L1 expression were observed following the sequential treatment. Conclusion The application of sequential treatment of PDT in combination with chemotherapy offers a promising therapeutic option for cancer treatment, by regulating the PD-L1 expression, autophagy, and non-mitochondrial pathways.

Background Studies have indicated that RIG-I may act as a tumor suppressor and participate in the tumorigenesis of some malignant diseases. However, RIG-I induces distinct cellular responses via different downstream signaling pathways depending on the cell type. The aim of this study was to investigate the biological function and underlying molecular mechanism of RIG-I in the tumorigenesis of melanoma. Methods We conducted RIG-I knockout and RIG-I overexpressing B16-F10 melanoma cell line, and further analyzed the RIG-I mediated change of tumor biology behaviors in spontaneous and poly I:C induced RIG-I activation status. Cell proliferation, cell cycle, apoptosis and migration were detected by CCK-8 assay, BrdU incorporation, Annexin V-PI staining assay and transwell assay, respectively. In vivo tumorigenicity was evaluated by tumor xenograft growth in nude mice and subsequently Ki67 staining and TUNEL assay. Furthermore, Western blot was utilized to explore the underlying mechanism of RIG-I in melanoma cells. Results Our data showed that RIG-I promotes the apoptosis and inhibits the proliferation by G1 phase cell-cycle arrest in B16-F10 melanoma cell line. Mechanically, RIG-I could induce the phosphorylation level of p38 MAPK and MAPK kinase MKK3/MKK4. Conclusion The current study demonstrated that RIG-I suppressed the development of melanoma via regulating the activity of MKK/p38 MAPK signaling pathway, which will be useful in the research of novel therapeutic targets for this malignant disease.

Identifying the young optically visible population in a star-forming region is essential for fully understanding the star formation event. In this paper, We identify 211 candidate members of the Perseus molecular cloud based on Gaia astronomy. We use LAMOST spectra to confirm that 51 of these candidates are new members, bringing the total census of known members to 856. The newly confirmed members are less extincted than previously known members. Two new stellar aggregates are identified in our updated census. With the updated member list, we obtain a statistically significant distance gradient of $\rm 4.84\;pc\;deg^{-1}$ from west to east. Distances and extinction corrected color-magnitude diagrams indicate that NGC 1333 is significantly younger than IC 348 and the remaining cloud regions. The disk fraction in NGC 1333 is higher than elsewhere, consistent with its youngest age. The star formation scenario in the Perseus molecular cloud is investigated and the bulk motion of the distributed population is consistent with the cloud being swept away by the Per-Tau Shell., Comment: 27 pages, 14 figures, 1 table; Accepted for publication in ApJ

We present a study of the size--mass relation for local post-starburst (PSB) galaxies at $z\lesssim0.33$ selected from the Sloan Digital Sky Survey Data Release 8. We find that PSB galaxies with stellar mass ($M_*$) at $10^9~M_{\odot}, Comment: 16 pages, 7 figures; accepted for publication in ApJ

A dual-functional nanosysterm is developed by means of Chlorin e6 (Ce6) as photosensitizer and 1,3-Diphenylisobenzofuran (DPBF) as fluorescent singlet oxygen (1O2) probe. Under 660 nm laser irradiation, Ce6 exhibites efficient 1O2 generation, and subsequently the production of 1O2 is assessed by the ratiometric fluorescence of PFO and DPBF under one-photon and two-photon excitation mode. The nanoparticles with excellent biocompatibility can be internalized into Hela cells and applied for tumor treatment. For intracellular PDT, the nanoparticles perform a high phototoxicity, while the PDT proccess can be evaluated in time by monitoring fluorescence signals of DPBF. This theranostic nanosysterm provides a facile strategy to fabricate 1O2-detection PDT, which can realize accurate and efficient photodynamic therapy based on singlet oxygen detection.

A disintegrin and metalloproteinase 3 (ADAM3) is a sperm membrane protein critical for sperm migration from the uterus into the oviduct and sperm-egg binding in mice. Disruption of PRSS37 results in male infertility concurrent with the absence of mature ADAM3 from cauda epididymal sperm. However, how PRSS37 modulates ADAM3 maturation remains largely unclear. Here, we determine the PRSS37 interactome by GFP immunoprecipitation coupled with mass spectrometry in PRSS37-EGFP knock-in mice. Three molecular chaperones (CLGN, CALR3 and PDILT) and three ADAM proteins (ADAM2, ADAM6B and ADAM4) were identified to be interacting with PRSS37. Coincidently, five of them (except ADAM4) have been reported to interact with ADAM3 precursor and regulate its maturation. We further demonstrated that PRSS37 also interacts directly with ADAM3 precursor and its deficiency impedes the association between PDILT and ADAM3. This could contribute to improper translocation of ADAM3 to the germ cell surface, leading to ADAM3 loss in PRSS37-null mature sperm. The understanding of the maturation mechanisms of pivotal sperm plasma membrane proteins will pave the way toward novel strategies for contraception and the treatment of unexplained male infertility.

To solve the problem of low parking efficiency and poor management in open temporary parking lots, a smart parking system was designed based on QR code and drone monitoring technologies. The system consists of four modules: parking spot QR code module, drone photography module, data processing module, and user interface module. Functional simulation of each module in the system was carried out by experiments with software programming. The capture of QR codes was achieved by fixed-point drone photography. Programmed with Python, the main system could successfully decipher QR codes, gather the occupancy status of parking spots and update the status as well. Then the user interface module could help users to make decisions on parking spots by presenting the parking status in different colors via a program written with Autoit3. The results show that this system is userfriendly, capable to be deployed at a low cost in a short time, and remains stable when running over a certain period. In the meantime, the occupancy status of the parking spots can be detected and recorded smoothly and readily, suggesting that this technology will have a wide range of applications in future.

We present the first results of an MMT/Hectospec campaign to measure the kinematics of globular clusters (GCs) around M49 -- the brightest galaxy in the Virgo galaxy cluster, which dominates the Virgo B subcluster. The data include kinematic tracers beyond 95 kpc (~5.2 effective radii) for M49 for the first time, enabling us to achieve three key insights reported here. First, beyond ~20'-30' (~100-150 kpc), the GC kinematics sampled along the minor photometric axis of M49 become increasingly hotter, indicating a transition from GCs related to M49 to those representing the Virgo B intra-cluster medium. Second, there is an anomaly in the line-of-sight radial velocity dispersion ($\sigma_{r,los}$) profile in an annulus ~10-15' (~50-90 kpc) from M49 in which the kinematics cool by $\Delta \sigma_{r,los}~150$ km s$^{-1}$ relative to those in- or outward. The kinematic fingerprint of a previous accretion event is hinted at in projected phase-space, and we isolate GCs that both give rise to this feature, and are spatially co-located with two prominent stellar shells in the halo of M49. Third, we find a subsample of GCs with velocities representative of the dwarf galaxy VCC1249 that is currently interacting with M49. The spatial distribution of these GCs closely resembles the morphology of VCC1249's isophotes, indicating that several of these GCs are likely in the act of being stripped from the dwarf during its passage through M49's halo. Taken together, these results point toward the opportunity of witnessing on-going giant halo assembly in the depths of a cluster environment., Comment: 14 pages, 9 figures, accepted for publication in ApJ

Based on the spectroscopic and shear catalogs for SDSS galaxies in the local Universe, we compare optically-selected active galactic nuclei (AGNs) with control star-forming and quiescent galaxies on galactic, inter-halo and larger scales. We find that AGNs are preferentially found in two specific stages of galaxy evolution: star-burst and `green valley' phases, and that the stellar population of their host galaxies is quite independent of stellar mass, different from normal galaxies. Combining galaxy-galaxy lensing and galaxy clustering on large scales, we measure the mass of AGN host halos. The typical halo mass is about $10^{12}h^{-1}\rm M_{\odot}$, similar to the characteristic mass in the stellar mass-halo mass relation (SHMR). For given stellar mass, AGN host galaxies and star-forming galaxies share the same SHMR, while quiescent galaxies have more massive halos. Clustering analysis on halo scales reveals that AGNs are surrounded by a larger number of satellites (with stellar mass down to 1/1000 of the mass of the central galaxy) than star-forming galaxies, and that galaxies with larger stellar velocity dispersion have more satellites. The number of satellites also increase with halo mass, reaching unity around $10^{12}h^{-1}\rm M_{\odot}$. Our results suggest a scenario, in which the interaction of the central galaxy with the satellites triggers an early episode of star burst and AGN activities, followed by multiple AGN cycles driven by the non-axisymmetric structure produced by the interaction. The feedback from the starburst and AGN reduces the amount of cold gas for fueling the central black hole, producing a characteristic halo mass scale, $\sim 10^{12}h^{-1}\rm M_{\odot}$, where the AGN fraction peaks., accepted by A&A, 17 pages, 11 figures

Fibroblast growth factor 9 (Fgf9) is a well-known factor that regulates bone development; however, its function in bone homeostasis is still unknown. Previously, we identified a point mutation in the FGF9 gene (p.Ser99Asn, S99N) and generated an isogeneic knock-in mouse model, which revealed that this loss-of-function mutation impaired early joint formation and was responsible for human multiple synostosis syndrome 3 (SYNS3). Moreover, newborn and adult S99N mutant mice exhibited significantly increased bone mass, suggesting that Fgf9 also participated in bone homeostasis. Histomorphology, tomography, and serological analysis of homozygous newborns and heterozygous adults showed that the Fgf9S99N mutation immensely increased bone mass and bone formation in perinatal and adult bones and decreased osteoclastogenesis in adult bone. An in vitro differentiation assay further revealed that the S99N mutation enhanced bone formation by promoting osteogenesis and mineralization of bone marrow mesenchymal stem cells (BMSCs) and attenuating osteoclastogenesis of bone marrow monocytes (BMMs). Considering the loss-of-function effect of the S99N mutation, we hypothesized that Fgf9 itself inhibits osteogenesis and promotes osteoclastogenesis. An in vitro differentiation assay revealed that Fgf9 prominently inhibited BMSC osteogenic differentiation and mineralization and showed for the first time that Fgf9 promoted osteoclastogenesis by enhancing preosteoclast aggregation and cell-cell fusion. Furthermore, specific inhibitors and in vitro differentiation assays were used and showed that Fgf9 inhibited BMSC osteogenesis mainly via the MEK/ERK pathway and partially via the PI3K/AKT pathway. Fgf9 also promoted osteoclastogenesis as a potential costimulatory factor with macrophage colony-stimating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) by coactivating the MAPK and PI3K/AKT signaling pathways. Taken together, our study demonstrated that Fgf9 is a negative regulator of bone homeostasis by regulating osteogenesis and osteoclastogenesis and provides a potential therapeutic target for bone degenerative diseases. © 2020 American Society for Bone and Mineral Research (ASBMR).