Hedgehog signaling regulates bone homeostasis through orchestrating osteoclast differentiation and osteoclast-osteoblast coupling.

Imbalance of bone homeostasis induces bone degenerative diseases such as osteoporosis. Hedgehog (Hh) signaling plays critical roles in regulating the development of limb and joint. However, its unique role in bone homeostasis remained largely unknown. Here, we found that canonical Hh signaling pathway was gradually augmented during osteoclast differentiation. Genetic inactivation of Hh signaling in osteoclasts, using Ctsk-Cre;Smof/f conditional knockout mice, disrupted both osteoclast formation and subsequent osteoclast-osteoblast coupling. Concordantly, either Hh signaling inhibitors or Smo/Gli2 knockdown stunted in vitro osteoclast formation. Mechanistically, Hh signaling positively regulated osteoclast differentiation via transactivation of Traf6 and stabilization of TRAF6 protein. Then, we identified connective tissue growth factor (CTGF) as an Hh-regulatory bone formation-stimulating factor derived from osteoclasts, whose loss played a causative role in osteopenia seen in CKO mice. In line with this, recombinant CTGF exerted mitigating effects against ovariectomy induced bone loss, supporting a potential extension of local rCTGF treatment to osteoporotic diseases. Collectively, our findings firstly demonstrate that Hh signaling, which dictates osteoclast differentiation and osteoclast-osteoblast coupling by regulating TRAF6 and CTGF, is crucial for maintaining bone homeostasis, shedding mechanistic and therapeutic insights into the realm of osteoporosis.

Satellite greenness and solar-induced chlorophyll fluorescence reveal reverse desertification in Gurbantunggut Desert.

The desertification reversal is a process of revegetation and natural restoration in fragile dryland areas due to human activities and climate change mediation. Understanding the impact of desertification reversion on terrestrial ecosystems, including vegetation greenness and photosynthetic capacity, is crucial for land policy-making and carbon-cycle model improvement. However, the phenomenon of desertification reversal is rarely mentioned in previous studies, which dramatically limits the understanding of vegetation dynamics in the arid area. Therefore, it is of great necessity to investigate the status of desertification reversal on the ecosystem in arid areas. In this study, we first reported the phenomenon of desertification reversion over the southern edge of the Gurbantunggut Desert through the Moderate-resolution Imaging Spectroradiometer classification map year by year. We discussed the consequences, ways, and causes of desertification reversion. Our results showed that the desertification reversal significantly increased vegetation greenness and photosynthetic capacity, which largely offset the negative impact of desertification on the ecosystem productivity; cropland expansion and grassland's natural restoration were the two main ways of desertification reversal; the improvement of soil-water condition was an essential environmental factor leading to the phenomenon of reverse desertification. This finding highlights the importance of desertification reversal in the carbon cycle of dryland ecosystems and prove that desertification reversal is an integral part of global and dryland vegetation greening.

Ammonia emission control in China would mitigate haze pollution and nitrogen deposition, but worsen acid rain.

China has been experiencing fine particle (i.e., aerodynamic diameters ≤ 2.5 µm; PM2.5) pollution and acid rain in recent decades, which exert adverse impacts on human health and the ecosystem. Recently, ammonia (i.e., NH3) emission reduction has been proposed as a strategic option to mitigate haze pollution. However, atmospheric NH3 is also closely bound to nitrogen deposition and acid rain, and comprehensive impacts of NH3 emission control are still poorly understood in China. In this study, by integrating a chemical transport model with a high-resolution NH3 emission inventory, we find that NH3 emission abatement can mitigate PM2.5 pollution and nitrogen deposition but would worsen acid rain in China. Quantitatively, a 50% reduction in NH3 emissions achievable by improving agricultural management, along with a targeted emission reduction (15%) for sulfur dioxide and nitrogen oxides, can alleviate PM2.5 pollution by 11-17% primarily by suppressing ammonium nitrate formation. Meanwhile, nitrogen deposition is estimated to decrease by 34%, with the area exceeding the critical load shrinking from 17% to 9% of China's terrestrial land. Nevertheless, this NH3 reduction would significantly aggravate precipitation acidification, with a decrease of as much as 1.0 unit in rainfall pH and a corresponding substantial increase in areas with heavy acid rain. An economic evaluation demonstrates that the worsened acid rain would partly offset the total economic benefit from improved air quality and less nitrogen deposition. After considering the costs of abatement options, we propose a region-specific strategy for multipollutant controls that will benefit human and ecosystem health.

Spatiotemporal trends of PM2.5 and its major chemical components at urban sites in Canada.

To evaluate the effectiveness of emission control regulations designed for reducing air pollution, chemically resolved PM2.5 data have been collected across Canada through the National Air Pollution Surveillance network in the past decade. 24-hr time integrated PM2.5 collected at seven urban and two rural sites during 2010-2016 were analyzed to characterize geographical and seasonal patterns and associated potential causes. Site-specific seven-year mean gravimetric PM2.5 mass concentrations ranged from 5.7 to 9.6 µg/m3. Seven-year mean concentrations of SO42-, NO3-, NH4+, organic carbon (OC), and elemental carbon (EC) were in the range of 0.68 to 1.6, 0.21 to 1.5, 0.27 to 0.71, 1.1 to 1.9, and 0.37 to 0.71 µg /m3, accounting for 10.8%-18.1%, 3.7%-16.7%, 4.7%-7.4%, 18.4%-21.0%, and 6.4%-10.6%, respectively, of gravimetric PM2.5 mass. PM2.5 and its five major chemical components showed higher concentrations in southeastern Canada and lower values in Atlantic Canada, with the seven-year mean ratios between the two regions being on the order of 1.7 for PM2.5 and 1.8-7.1 for its chemical components. When comparing the concentrations between urban and rural sites within the same region, those of SO42- and NH4+ were comparable, while those of NO3-, OC, and EC were around 20%, 40%-50%, and 70%-80%, respectively, higher at urban than rural sites, indicating the regional scale impacts of SO42- and NH4+ and effects of local sources on OC and EC. Monthly variations generally showed summertime peaks for SO42- and wintertime peaks for NO3-, but those of NH4+, OC, and EC exhibited different seasonality at different locations.

Recent Advances in the Development of Water Oxidation Electrocatalysts at Mild pH.

Developing anodic oxygen evolution reaction (OER) electrocatalysts with high catalytic activities is of great importance for effective water splitting. Compared with the water-oxidation electrocatalysts that are commonly utilized in alkaline conditions, the ones operating efficiently under neutral or near neutral conditions are more environmentally friendly with less corrosion issues. This review starts with a brief introduction of OER, the importance of OER in mild-pH media, as well as the fundamentals and performance parameters of OER electrocatalysts. Then, recent progress of the rational design of electrocatalysts for OER in mild-pH conditions is discussed. The chemical structures or components, synthetic approaches, and catalytic performances of the OER catalysts will be reviewed. Some interesting insights into the catalytic mechanism are also included and discussed. It concludes with a brief outlook on the possible remaining challenges and future trends of neutral or near-neutral OER electrocatalysts. It hopefully provides the readers with a distinct perspective of the history, present, and future of OER electrocatalysts at mild conditions.

Oxygen Vacancies of Cr-Doped CeO2 Nanorods That Efficiently Enhance the Performance of Electrocatalytic N2 Fixation to NH3 under Ambient Conditions.

Producing ammonia (NH3) by electrocatalytic N2 fixation is a promising and environmentally friendly strategy, in comparison to the Haber-Bosch process with high consumption of energy and CO2 emissions. Because of the extremely high bond energy, it is indispensable to explore valid catalysts to activate the triple bond. In this paper, Cr-doped CeO2 nanorods are developed to serve as non-noble-metal electrocatalysts for an electrocatalytic N2 reduction reaction. Introducing Cr into the catalyst leads to an increase of the oxygen vacancies. In a 0.1 M Na2SO4 solution, the Cr0.1CeO2 nanorods achieve a high Faradaic efficiency (3.84%) and a large NH3 yield (16.82 µg h-1 mgcat.-1) at -0.7 V versus reversible hydrogen electrode. The Cr0.1CeO2 nanorods also exhibit high stability during the reaction.

In Situ Hydrothermal Growth of TiO2 Nanoparticles on a Conductive Ti3C2T x MXene Nanosheet: A Synergistically Active Ti-Based Nanohybrid Electrocatalyst for Enhanced N2 Reduction to NH3 at Ambient Conditions.

The traditional power-wasting Haber-Bosch process still dominates industrial NH3 production. Recent years witnessed the rapid development of an electrochemical N2 reduction reaction (NRR) because of its environmentally benign and sustainable feature. Here, we demonstrate the first utilization of a Ti3C2T x MXene nanosheet as both the precursor and conductive substrate toward the in situ hydrothermal growth of TiO2 nanoparticles. The marriage of TiO2 and Ti3C2T x leads to a synergistically active Ti-based nanohybrid catalyst that can strengthen N2 reduction electrocatalysis. When tested in 0.1 M HCl, such a TiO2/Ti3C2T x hybrid is superior in catalytic performance, capable of affording a NH3 yield of 26.32 µg h-1 mg-1cat. with a 8.42% Faradaic efficiency (FE) at -0.60 V versus reversible hydrogen electrode (RHE), larger than those for TiO2 and Ti3C2T x. Notably, this nanohybrid also shows good NH3 selectivity with high electrochemical durability.

Ni2P Nanosheets on Carbon Cloth: An Efficient Flexible Electrode for Sodium-Ion Batteries.

Transition-metal phosphides have been increasingly investigated because of their high theoretical specific capacity and low potential for sodium storage. Herein, we describe the development of Ni2P nanosheets on carbon cloth (Ni2P Ns/CC), which behaves as a flexible 3D anode for sodium-ion batteries. Such a Ni2P Ns/CC delivers a high capacity of 399 mA h g-1 at 0.2 A g-1. At 2 A g-1, it still delivers 72 mA h g-1 even after 1000 cycles. The impressive performance is attributed to such a self-supported structure. Moreover, a possible conversion reaction mechanism is also carefully revealed.

Effects of 1.8 GHz radiofrequency field on microstructure and bone metabolism of femur in mice.

To investigate the effects of 1.8 GHz radiofrequency (RF) field on bone microstructure and metabolism of femur in mice, C57BL/6 mice (male, age 4 weeks) were whole-body exposed or sham exposed to 1.8 GHz RF field. Specific absorption rates of whole body and bone were approximately 2.70 and 1.14 W/kg (6 h/day for 28 days). After exposure, microstructure and morphology of femur were observed by microcomputed tomography (micro-CT), Hematoxylin and Eosin (HE) and Masson staining. Subsequently, bone parameters were calculated directly from the reconstructed images, including structure model index, bone mineral density, trabecular bone volume/total volume, connectivity density, trabecular number, trabecular thickness, and trabecular separation. Biomarkers that reflect bone metabolism, such as serum total alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase 5b (TRACP-5b), were determined by biochemical assay methods. Micro-CT and histology results showed that there was no significant change in bone microstructure and the above parameters in RF group, compared with sham group. The activity of serum ALP and BALP increased 29.47% and 16.82%, respectively, in RF group, compared with sham group (P < 0.05). In addition, there were no significant differences in the activity of serum TRACP-5b between RF group and sham group. In brief, under present experimental conditions, we did not find support for an effect of 1.8 GHz RF field on bone microstructure; however, it might promote metabolic function of osteoblasts in mice. Bioelectromagnetics. 39:386-393, 2018. © 2018 Wiley Periodicals, Inc.

Effects of aerosol water content and acidity on the light absorption of atmospheric humic-like substances in winter.

Atmospheric humic-like substances (HULIS) could affect regional climate due to their strong light-absorbing capacity. Daily fine particulate matter (PM2.5) samples were collected from December 18, 2016 to January 8, 2017 at an urban site in Chongqing, Southwest China. The mean concentration of HULIS in terms of carbon (HULIS-C) was 6.4 ± 3.4 µg m-3, accounting for 72% of water-soluble organic carbon. The mass absorption efficiency at 365 nm (MAE365) and absorption Ångström index (AAE) of atmospheric HULIS were 2.8 ± 0.30 m2 g-1 C and 4.6 ± 0.37, respectively. Good correlations between the light absorption coefficients of HULIS at 365 nm (Abs365) and the concentrations of K+, elemental carbon, NO3-, and NH4+ were observed, with correlation coefficients higher than 0.83, indicating that biomass burning and secondary formation were potential sources of light-absorbing HULIS, as evidenced by abundant fluorescent components related to less-oxygenated HULIS. Comparing the changes in Abs365 values, concentrations of major water-soluble inorganic ions and carbonaceous compounds in PM2.5, and environmental factors during the clean and pollution periods, we found that extensive biomass burning during the pollution period contributed significantly to the increase of Abs365 values. Moreover, the aerosol pH during the pollution period was close to 4, and NO2 concentration and aerosol water content were about 1.6 and 2.7 times higher than those during the clean period, respectively, which were favorable to form secondary HULIS through aqueous phase reactions in the presence of high NOx, resulting in an evident increase in its light absorption. Knowledge generated from this study is critical for evaluating the regional radiative forcing of brown carbon in southwest China.

Fabrication of an Optoplasmonic Raft with Improved SERS Performance Detecting Methamphetamine through Bubble Enrichment.

In this work, a novel raft-like structure that combines noble metal nanoparticles (NPs) with an interconnected layer of hemispherical dielectric shell was fabricated and characterized. It was discovered that this hybrid material can enhance the optoplasmonic interaction between plasmonic and dielectric components, thereby improving the sensing performance in surface-enhanced Raman spectroscopy (SERS). Varied geometric parameters of the fabricated optoplasmonic raft, including the inner diameter and thickness of the dielectric shell, were attempted and analyzed through numerical simulation and experimental SERS measurements. With particular size, thickness, and incident orientation, the silica shell focuses the incident optical flow into the deposited silver NPs, undergoing similar near-field focusing behavior in comparison with other optoplasmonic entities. This optoplasmonic raft floating on the water surface is able to harvest the target molecules effectively through bubble enrichment, which rapidly captures and concentrates analytes from the aqueous phase. With a limited sampling time, the sensing performance of the developed optoplasmonic raft is improved by applying the optimized parameters involved in bubble enrichment. The substrates and corresponding enrichment method were implemented in the detection of methamphetamine (METH), achieving a limit of detection (LOD) down to 0.035 nM. As for practical onsite detection, the developed substrate and bubbling strategy were applied in an assembled set, employing a portable Raman spectrometer and an air pump. This set is able to detect METH dissolved in regular commercial beer, which is quite competent in the investigation of drug abuse.

[Analysis of three-dimensional fluorescence overlapping spectra using differential spectra and independent component analysis].

The analysis of multi-component three-dimensional fluorescence overlapping spectra is always very difficult. In view of the advantage of differential spectra and based on the calculation principle of two-dimensional differential spectra, the three-dimensional fluorescence spectra with both excitation and emission spectra is fully utilized. Firstly, the excitation differential spectra and emission differential spectra are respectively computed after unfolding the three-dimensional fluorescence spectra. Then the excitation differential spectra and emission differential spectra of the single component are obtained by analyzing the multicomponent differential spectra using independent component analysis. In this process, the use of cubic spline increases the data points of excitation spectra, and the roughness penalty smoothing reduces the noise of emission spectra which is beneficial for the computation of differential spectra. The similarity indices between the standard spectra and recovered spectra show that independent component analysis based on differential spectra is more suitable for the component recognition of three-dimensional fluorescence overlapping spectra.

Trends of inorganic sulfur and nitrogen species at an urban site in western Canada (2004-2018).

A 15-year (2004-2018) record of measurement data of gaseous and particulate sulfur and nitrogen pollutants in air collected at an urban site in Burnaby in western Canada was analyzed for generating their decadal trends using three different methods, including linear regression, Mann-Kendall test and Theil-Sen trend estimator (MK-TS), and ensemble empirical mode decomposition (EEMD). Annual mean concentration of SO2 and SO42- decreased by about 59% and 42%, respectively, during the 15-year period. The slower decreases of SO42- than SO2 were mainly caused by the increased O3 concentration and temperature in spring and summer, which promoted conversion of SO2 to SO42- through gas-phase reaction, and by the increased aerosol pH value and availability of H2O2 in winter, which enhanced aqueous-phase SO42- formation. Accordingly, the sulfur oxidation ratio (SOR) increased by 23% or more in spring, summer, and winter during the 15-year period. Annual mean concentrations of NO2 and NO3- declined by 36% and 38%, respectively, during this period. On seasonal basis, NO3- decreased faster than NO2 in autumn and slower in winter. The non-linear responses of NO3- to NO2 concentration decreases were more evident in winter than the other seasons, partly due to the increased particulate NO3- fraction caused by decreased temperature, increased aerosol pH value, and enhanced NO3- formation caused by increased O3 concentrations. Annual mean concentration of NH3 showed small increases due to stable NH3 emission and reduced conversion of NH3 to NH4+. NH4+ concentration decreased by 51% during the 15-year period. These results suggest that reduced oxidants levels are likely responsible for weakened formation of secondary inorganic aerosols, besides emission reductions for SO2 and NO2.

Preparation and Closed-Loop Recycling of Ultra-High-Filled Wood Flour/Dynamic Polyurethane Composites.

The development of biomass-based composites has greatly reduced the daily consumption of plastics. However, these materials are rarely recyclable, thus, posing a severe threat to the environment. Herein, we designed and prepared novel composite materials with ultra-high biomass (i.e., wood flour) filling capacity and good closed-loop recycling properties. The dynamic polyurethane polymer was polymerized in situ on the surface of wood fiber, and then they were hot-pressed into composites. Fourier-transform infrared (FTIR), scanning electron microscopy (SEM), and dynamic thermomechanical analysis (DMA) measurements reveal good compatibility between the polyurethane and wood flour in the composites when the wood flour content is ≤80 wt%. The maximum tensile and bending strength of the composite are 37 and 33 MPa when the wood flour content is 80%. The higher wood flour content results in higher thermal expansion stability and creep resistance in the composites. Moreover, the thermal debonding of dynamic phenol-carbamate bonds facilitates the composites to undergo physical and chemical cycling. The recycled and remolded composites exhibit good mechanical property recovery rates and retain the chemical structures of the original composites.

SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis.

Mitochondrial dysfunction plays a major role in the development of intervertebral disc degeneration (IDD). Sirtuin 5 (SIRT5) participates in the maintenance of mitochondrial homeostasis through its desuccinylase activity. However, it is still unclear whether succinylation or SIRT5 is involved in the impairment of mitochondria and development of IDD induced by excessive mechanical stress. Our 4D label-free quantitative proteomic results showed decreased expression of the desuccinylase SIRT5 in rat nucleus pulposus (NP) tissues under mechanical loading. Overexpression of Sirt5 effectively alleviated, whereas knockdown of Sirt5 aggravated, the apoptosis and dysfunction of NP cells under mechanical stress, consistent with the more severe IDD phenotype of Sirt5 KO mice than wild-type mice that underwent lumbar spine instability (LSI) surgery. Moreover, immunoprecipitation-coupled mass spectrometry (IP-MS) results suggested that AIFM1 was a downstream target of SIRT5, which was verified by a Co-IP assay. We further demonstrated that reduced SIRT5 expression resulted in the increased succinylation of AIFM1, which in turn abolished the interaction between AIFM1 and CHCHD4 and thus led to the reduced electron transfer chain (ETC) complex subunits in NP cells. Reduced ETC complex subunits resulted in mitochondrial dysfunction and the subsequent occurrence of IDD under mechanical stress. Finally, we validated the efficacy of treatments targeting disrupted mitochondrial protein importation by upregulating SIRT5 expression or methylene blue (MB) administration in the compression-induced rat IDD model. In conclusion, our study provides new insights into the occurrence and development of IDD and offers promising therapeutic approaches for IDD.

Identification of decadal trends and associated causes for organic and elemental carbon in PM2.5 at Canadian urban sites.

Chemically resolved data for fine particulate matter (PM2.5) have been collected across Canada since 2003 through the National Air Pollution Surveillance (NAPS) network. Seven urban sites that have 10-17 years (2003-2019) of PM2.5 organic carbon (OC) and elemental carbon (EC) data were selected for analysis of decadal trends of OC, EC, and OC/EC ratio using the Ensemble Empirical Mode Decomposition method. Results showed that OC and EC decreased by 0.009-0.072 µg m-3 yr-1 and 0.028-0.049 µg m-3 yr-1, or 0.77-3.1 % yr-1 and 3.2-6.7 % yr-1, respectively, depending on the location. The more rapid decrease in EC than OC resulted in an increasing trend in the OC/EC ratio of 0.03-0.19 yr-1 across the sites. Macro-tracer approach was used to estimate source attributions of OC and EC from wood burning, fossil fuel combustion, and secondary aerosol formation. Using this approach, it was identified that the significant decrease in EC during the past decade was predominately caused by reduced on-road emissions. The decreased emissions from wood burning and transportation dominated the decline of OC, but such a decline was largely offset by the enhanced secondary organic aerosol (SOA) formation, resulting in much weaker decline of OC than EC. The enhanced SOA formation was due to the increased biogenic emissions fully offsetting the decreased anthropogenic emissions for volatile organic compounds. These findings highlight the need for quantifying biogenic sources of VOCs and other oxidants that are involved in OC formation at the national scale.

Non-Isothermal Crystallization of Titanium-Dioxide-Incorporated Rice Straw Fiber/Poly(butylene succinate) Biocomposites.

In this work, titanium dioxide (TiO2)-incorporated rice straw fiber (RS)/poly(butylene succinate) (PBS) biocomposites were prepared by injection molding with different TiO2 powder loadings. The RS/PBS with 1 wt% TiO2 demonstrated the best mechanical properties, where the flexural strength and modulus increased by 30.34% and 28.39%, respectively, compared with RS/PBS. The non-isothermal crystallization of neat PBS, RS/PBS composites, and titanium-dioxide-incorporated RS/PBS composites was investigated by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The non-isothermal crystallization data were analyzed using several theoretical models. The Avrami and Mo kinetic models described the non-isothermal crystallization behavior of neat PBS and the composites; however, the Ozawa model was inapplicable. The crystallization temperature (Tc), half-time of crystallization (t1/2), and kinetic parameters (FT) showed that the crystallizability followed the order: TiO2-incorporated RS/PBS composites > RS/PBS > PBS. The RS/PBS with 1 wt% TiO2 showed the best crystallization properties. The Friedman model was used to evaluate the effective activation energy of the non-isothermal crystallization of PBS and its composites. Rice straw fiber and TiO2 acted as nucleating agents for PBS. The XRD results showed that the addition of rice straw fiber and TiO2 did not substantially affect the crystal parameters of the PBS matrix. Overall, this study shows that RS and TiO2 can significantly improve the crystallization and mechanical properties of PBS composites.

Consumption of common illicit drugs in twenty-one cities in southwest China through wastewater analysis.

Wastewater-based epidemiology (WBE) was applied to estimate illicit drugs consumption at a provincial scale in southwest China. A large-scale wastewater sampling campaign was carried out from October to November in 2021 in 156 different wastewater treatment plants (WWTPs). Two 24-h composite influent wastewater samples were collected in each WWTP. Concentrations of 11 illicit drugs or their metabolites were determined using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Benzoylecgonine, cocaine, 6-monoacetylmorphine, norketamine, 3,4-methylenedioxymethamphetamine (MDMA), and MDA were not detected in any of the wastewater samples. Methamphetamine and morphine were detected in >84% of samples, while ketamine was found in about 6% of the samples. The city-specific population-weighted consumption of methamphetamine and ketamine were in the range of 0.6-49.7 and N.D.-7.0 mg 1000 inh-1 day-1, respectively, with provincial population-weighted values of 22.6 and 2.4 mg 1000 inh-1 day-1 in southwest China. The city-specific load of morphine varied from 3.2 to 10.2 mg 1000 inh-1 day-1, with provincial population-weighted load of 6.7 mg 1000 inh-1 day-1. Taking into account therapeutic use of morphine and codeine, the provincial heroin consumption was estimated to be 10.3 mg 1000 inh-1 day-1, ranging from 1.7 to 18.5 mg 1000 inh-1 day-1 in 21 cities. Overall, the patterns of illicit drugs use were similar across southwest China, with high prevalence of methamphetamine and heroin, but relatively low use of ketamine. These findings could provide accurate drugs consumption information for timely identifying potential hotspots of illicit drugs use in southwest China.

Hedgehog signaling orchestrates cartilage-to-bone transition independently of Smoothened.

Although recent lineage studies strongly support a chondrocyte-to-osteoblast differentiation continuum, the biological significance and molecular basis remain undetermined. In silico analysis at a single-cell level indicates a transient shutdown of Hedgehog-related transcriptome during simulated cartilage-to-bone transition. Prompted by this, we genetically induce gain- and loss-of function to probe the role of Hedgehog signaling in cartilage-to-bone transition. Ablating Smo in hypertrophic chondrocytes (HCs) does not result in any phenotypic outcome, whereas deleting Ptch1 in HCs leads to disrupted formation of primary spongiosa and actively proliferating HCs-derived osteogenic cells that contribute to bony bulges seen in adult mutant mice. In HCs-derived osteoblasts, constitutive activation of Hedgehog signaling blocks their further differentiation to osteocytes. Moreover, ablation of both Smo and Ptch1 in HCs reverses neither persistent Hedgehog signaling nor bone overgrowths. These results establish a functional contribution of extended chondrocyte lineage to bone homeostasis and diseases, governed by an unanticipated mode of regulation for Hedgehog signaling independently of Smo.

XMU-MP-1 attenuates osteoarthritis via inhibiting cartilage degradation and chondrocyte apoptosis.

Osteoarthritis (OA) is the most prevalent type of degenerative joint disease; it is reported to be associated with inflammatory responses, chondrocyte apoptosis, and cartilage degeneration. XMU-MP-1 is a selective MST1/2 inhibitor which activates the downstream effector YAP and promotes cell growth. It has displayed excellent benefits in mouse intestinal repair, as well as liver repair and regeneration. However, the effects of XMU-MP-1 on OA remain unclear. In this study, we investigated the therapeutic role of XMU-MP-1 on interleukin-1ß (IL-1ß)-induced inflammation in mice chondrocytes and the destabilization of the medial meniscus surgery (DMM)-induced OA model. In chondrocytes, treatment with XMU-MP-1 elevated the matrix metalloproteinases (Mmp3, Mmp13) and decreased the extracellular matrix (Col2, Acan) induced by IL-1ß. Moreover, XMU-MP-1 strongly inhibited IL-1ß-induced chondrocyte apoptosis and significantly promoted chondrocyte proliferation. Furthermore, XMU-MP-1 demonstrated a protective and therapeutic influence on the mouse OA model. These findings indicate that XMU-MP-1 may have a protective effect on cartilage degradation and may be a new potential therapeutic option for OA.