An Effective GNSS/PDR Fusion Positioning Algorithm on Smartphones for Challenging Scenarios.

The location-based smartphone service brings new development opportunities for seamless indoor/outdoor positioning. However, in complex scenarios such as cities, tunnels, overpasses, forests, etc., using only GNSS on smartphones cannot provide stable and reliable positioning results. Usually, additional sensors are needed to assist GNSS. This paper investigates the GNSS positioning algorithm assisted by pedestrian dead reckoning (PDR) in complex scenarios. First, we introduce a step detection algorithm based on the peak-valley of acceleration modulus, and the Weinberg model and the Mahony algorithm in PDR are used to estimate step length and heading. On this basis, we evaluated the performance of GNSS/PDR fusion positioning in an open scenario, a semiopen scenario, and a blocked scenario, respectively. Finally, we develop a GNSS/PDR real-time positioning software, called China University of Mining and Technology-POSitioning (CUMT-POS) version 1.0, on the Android 10 platform. By comparing GNSS solutions, PDR solutions, GNSS/PDR solutions, and real-time kinematic (RTK) solutions, we verify the potential auxiliary ability of PDR for GNSS positioning in complex environments, proving that multisource sensor fusion positioning significantly improves reliability and stability. Our research can help the realization of urban informatization and smart cities.

Golgi Apparatus-Targeted Photodynamic Therapy for Enhancing Tumor Immunogenicity by Eliciting NLRP3 Protein-Dependent Pyroptosis.

Innate and adaptive immunity is important for initiating and maintaining immune function. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves as a checkpoint in innate and adaptive immunity, promoting the secretion of pro-inflammatory cytokines and gasdermin D-mediated pyroptosis. As a highly inflammatory form of cell death distinct from apoptosis, pyroptosis can trigger immunogenic cell death and promote systemic immune responses in solid tumors. Previous studies proposed that NLRP3 was activated by translocation to the mitochondria. However, a recent authoritative study has challenged this model and proved that the Golgi apparatus might be a prerequisite for the activation of NLRP3. In this study, we first developed a Golgi apparatus-targeted photodynamic strategy to induce the activation of NLRP3 by precisely locating organelles. We found that Golgi apparatus-targeted photodynamic therapy could significantly upregulate NLRP3 expression to promote the subsequent release of intracellular proinflammatory contents such as IL-1ß or IL-18, creating an inflammatory storm to enhance innate immunity. Moreover, this acute NLRP3 upregulation also activated its downstream classical caspase-1-dependent pyroptosis to enhance tumor immunogenicity, triggering adaptive immunity. Pyroptosis eventually led to immunogenic cell death, promoted the maturation of dendritic cells, and effectively activated antitumor immunity and long-lived immune memory. Overall, this Golgi apparatus-targeted strategy provided molecular insights into the occurrence of immunogenic pyroptosis and offered a platform to remodel the tumor microenvironment.

Precise manipulation of circadian clock using MnO2 nanocapsules to amplify photodynamic therapy for osteosarcoma.

Circadian rhythm (CR) disruption contributes to tumor initiation and progression, however the pharmacological targeting of circadian regulators reversely inhibits tumor growth. Precisely controlling CR in tumor cells is urgently required to investigate the exact role of CR interruption in tumor therapy. Herein, based on KL001, a small molecule that specifically interacts with the clock gene cryptochrome (CRY) functioning at disruption of CR, we fabricated a hollow MnO2 nanocapsule carrying KL001 and photosensitizer BODIPY with the modification of alendronate (ALD) on the surface (H-MnSiO/K&B-ALD) for osteosarcoma (OS) targeting. The H-MnSiO/K&B-ALD nanoparticles reduced the CR amplitude in OS cells without affecting cell proliferation. Furthermore, nanoparticles-controlled oxygen consumption by inhibiting mitochondrial respiration via CR disruption, thus partially overcoming the hypoxia limitation for photodynamic therapy (PDT) and significantly promoting PDT efficacy. An orthotopic OS model demonstrated that KL001 significantly enhanced the inhibitory effect of H-MnSiO/K&B-ALD nanoparticles on tumor growth after laser irradiation. CR disruption and oxygen level enhancement induced by H-MnSiO/K&B-ALD nanoparticles under laser irradiation were also confirmed in vivo. This discovery first demonstrated the potential of CR controlling for tumor PDT ablation and provided a promising strategy for overcoming tumor hypoxia.

Deep learning of bone metastasis in small cell lung cancer: A large sample-based study.

Introduction: Bone is a common metastatic site for small cell lung cancer (SCLC). Bone metastasis (BM) in patients have are known to show poor prognostic outcomes. We explored the epidemiological characteristics of BM in SCLC patients and create a new deep learning model to predict outcomes for cancer-specific survival (CSS) and overall survival (OS). Materials and Methods: Data for SCLC patients diagnosed with or without BM from 2010 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox proportional hazards regression models were used to evaluate the effects of prognostic variables on OS and CSS. Through integration of these variables, nomograms were created for the prediction of CSS and OS rates at 3-month,6- month,and 12-month. Harrell's coordination index, calibration curves,and time- dependent ROC curves were used to assess the nomograms' accuracy. Decision tree analysis was used to evaluate the clinical application value of the established nomogram. Results: In this study, 4201 patients were enrolled. Male sex, tumor size 25 but <10, brain and liver metastases, as well as chemotherapy were associated with a high risk for BM. Tumor size, Age, N stage, gender, liver metastasis, radiotherapy as well as chemotherapy were shown to be prognostic variables for OS, and the prognostic variables for CSS were added to the tumor number in addition. Based on these results, nomograms for CSS and OS were established separately. Internal as well as external validation showed that the C-index, calibration cuurve and DCA had good constructive correction effect and clinical application value. Decision tree analysis further confirmed the prognostic factors of OS and CSS. Discussion: The nomogram and decision tree models developed in this study effectively guided treatment decisions for SCLC patients with BM. The creation of prediction models for BM SCLC patients may be facilitated by deep learning models.

Piezoresistive MXene/Silk fibroin nanocomposite hydrogel for accelerating bone regeneration by Re-establishing electrical microenvironment.

The electrical microenvironment plays an important role in bone repair. However, the underlying mechanism by which electrical stimulation (ES) promotes bone regeneration remains unclear, limiting the design of bone microenvironment-specific electroactive materials. Herein, by simple co-incubation in aqueous suspensions at physiological temperatures, biocompatible regenerated silk fibroin (RSF) is found to assemble into nanofibrils with a ß-sheet structure on MXene nanosheets, which has been reported to inhibit the restacking and oxidation of MXene. An electroactive hydrogel based on RSF and bioencapsulated MXene is thus prepared to promote efficient bone regeneration. This MXene/RSF hydrogel also acts as a piezoresistive pressure transducer, which can potentially be utilized to monitor the electrophysiological microenvironment. RNA sequencing is performed to explore the underlying mechanisms, which can activate Ca2+/CALM signaling in favor of the direct osteogenesis process. ES is found to facilitate indirect osteogenesis by promoting the polarization of M2 macrophages, as well as stimulating the neogenesis and migration of endotheliocytes. Consistent improvements in bone regeneration and angiogenesis are observed with MXene/RSF hydrogels under ES in vivo. Collectively, the MXene/RSF hydrogel provides a distinctive and promising strategy for promoting direct osteogenesis, regulating immune microenvironment and neovascularization under ES, leading to re-establish electrical microenvironment for bone regeneration.

Precisely Targeted Nano-Controller of PD-L1 Level for Non-Small Cell Lung Cancer Spinal Metastasis Immunotherapy.

Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin ß3 (ß3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target ß3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM.

Siglec15 Checkpoint Blockade for Simultaneous Immunochemotherapy and Osteolysis Inhibition in Lung Adenocarcinoma Spinal Metastasis via a Hollow Nanoplatform.

Low responsiveness to anti-programmed death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) for solid tumors indicates the presence of other immunosuppressive pathways. Siglec15, a newly discovered immune checkpoint, has been reported to repress immune responses in the tumor microenvironment (TME) and regulate osteoclast differentiation. However, the role of Siglec15 in the treatment for bone metastasis remains unclear. Herein, Siglec15 shows significantly higher expression in lung adenocarcinoma spinal metastasis (LUAD-SM) than in para-cancerous spinal tissues and primary LUAD. Subsequently, a TME-responsive hollow MnO2 nanoplatform (H-M) loaded with Siglec15 siRNA and cisplatin (H-M@siS15/Cis) is developed, and the surface is modified with an aspartic acid octapeptide (Asp8 ), thus allowing H-M to target spinal metastasis. High drug-loading capacity, good biocompatibility, effective tumor accumulation, and efficient Siglec15 silencing are demonstrated. Furthermore, the nanoparticles could reverse immunosuppression caused by tumor cells and tumor-associated macrophages (TAMs) and inhibit osteoclast differentiation via Siglec15 downregulation in vitro. In a LUAD-SM mouse model, H-M@siS15/Cis-Asp8 exhibits superior therapeutic efficacy via synergetic immunochemotherapy and osteolysis inhibition. Taken together, this single nanoplatform reveals the therapeutic potential of the new immune checkpoint Siglec15 in LUAD-SM and provides a strategy to treat this disease.

Siglec15 facilitates the progression of non-small cell lung cancer and is correlated with spinal metastasis.

Background: Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, leading to poor prognosis. Siglec15 has been identified as a newly discovered immune checkpoint and exists in a variety of tumors. However, the expression and function of Siglec15 in NSCLC and bone metastasis remains largely unclear. Methods: Siglec15 expression in NSCLC and the correlation between Siglec15 expression and the clinicopathological factors of patients with NSCLC were analyzed using The Cancer Genome Atlas (TCGA) dataset. Correlation analysis between Siglec15 and bone metastasis-related genes expression was based on the Molecular Signatures Database (MSigDB). Western blotting and immunohistochemistry were applied to detect Siglec15 expression in NSCLC and spinal metastasis. Human A549 and mouse CMT167 cells were transfected with Siglec15 siRNA to investigate its biological functions in NSCLC proliferation, migration, and invasion. The immune-related signaling pathways and correlations between Siglec15 and tumor-infiltrating immune cells and different immune checkpoints in the NSCLC tumor microenvironment (TME) were analyzed using Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and gene set enrichment analysis (GSEA). To demonstrate Siglec15 in NSCLC cell-mediated T cell suppression and investigate the potential mechanism of Siglec15 silencing in antitumor immunity, we used a T cell killing assay in vitro and the high­throughput sequencing approach. Results: Siglec15 expression was positively associated with the tumor stage and lymph node metastasis, and was markedly up-regulated in NSCLC bone metastasis. Functionally, Siglec15 knockdown inhibited the proliferation, migration, and invasion of NSCLC cells (A549 and CMT167 cell lines). A total of eight kinds of tumor-infiltrating immune cells were found to have a strong association with the Siglec15 expression in NSCLC cases. The expression of previously discovered immune checkpoints was higher in the high Siglec15 expression NSCLC group. Furthermore, an in vitro T cell killing assay showed that the down-regulation of Siglec15 in tumor cells could enhance the antitumor immune responses of CD8+ T cells. High­throughput sequencing revealed the potential molecular mechanisms underlying the Siglec15-mediated immunosuppression effect of tumor cells on immune cells. Conclusions: Siglec15 may be involved in the pathogenesis of spinal metastasis in NSCLC and provide a new potential therapeutic target for the treatment of NSCLC and bone metastasis.

Enhancement of anti-PD-1/PD-L1 immunotherapy for osteosarcoma using an intelligent autophagy-controlling metal organic framework.

Poor immunogenicity and compromised T cell infiltration impede the application of immune-checkpoint blockade (ICB) immunotherapy for osteosarcoma (OS). Although autophagy is involved in enhancing the immune response, the synergistic role of autophagy in ICB immunotherapy and the accurate control of autophagy levels in OS remain elusive and challenging. Here, we designed a pH-sensitive autophagy-controlling nanocarrier, CUR-BMS1166@ZIF-8@PEG-FA (CBZP), loading a natural derivative, curcumin (CUR), to boost the immunotherapeutic response of PD-1/PD-L1 blockade by activating immunogenic cell death (ICD) via autophagic cell death, and BMS1166 to inhibit the PD-1/PD-L1 interaction simultaneously, enhancing the tumor immunogenicity and sensitizing the antitumor T cell immunity. After entering tumor cells, the pH-sensitive nanoparticles induced autophagy and decreased the intracellular pH, which in turn further facilitated the release of CUR to enhance autophagic activity. Transferring CBZP to orthotopic OS tumor-bearing mice showed powerful antitumor effects and established long-term immunity against tumor recurrence, accompanied by enhanced dendritic cell maturation and tumor infiltration of CD8+ T lymphocytes. Collectively, CBZP exhibited synergistic effects in treating OS by combining ICD induction with checkpoint blockade, thereby shedding light on the use of autophagy control as a potential clinical therapy for OS.

Detection of collagen by multi-wavelength photoacoustic analysis as a biomarker for bone health assessment.

Collagen is an important biomarker of osteoporosis progression. Noninvasive, multispectral, photoacoustic (PA) techniques use pulsed laser light to induce PA signals to facilitate the visualization of chemical components that are strongly related to tissue health. In this study, the feasibility of multi-wavelength PA (MWPA) measurement of the collagen in bone, using the wavelength range of 1300-1800 nm, was investigated. First, the feasibility of this approach for detecting the collagen content of bone was demonstrated by means of numerical simulation. Then, ex vivo experiments were conducted on both animal and human bone specimens with different bone densities using the MWPA method. The relative collagen content was extracted and compared with the results of micro-computed tomography (micro-CT) and histology. The results showed that the "relative collagen content" parameter obtained using the MWPA approach correlated well with the bone volume ratio obtained from micro-CT images and histological analysis results. This study highlights the potential of the proposed PA technique for determining the collagen content of bones as a biomarker for bone health assessment.

Effects of Mechanical Compression on Chondrogenesis of Human Synovium-Derived Mesenchymal Stem Cells in Agarose Hydrogel.

Mechanical compression is a double-edged sword for cartilage remodeling, and the effect of mechanical compression on chondrogenic differentiation still remains elusive to date. Herein, we investigate the effect of mechanical dynamic compression on the chondrogenic differentiation of human synovium-derived mesenchymal stem cells (SMSCs). To this aim, SMSCs encapsulated in agarose hydrogels were cultured in chondrogenic-induced medium with or without dynamic compression. Dynamic compression was applied at either early time-point (day 1) or late time-point (day 21) during chondrogenic induction period. We found that dynamic compression initiated at early time-point downregulated the expression level of chondrocyte-specific markers as well as hypertrophy-specific markers compared with unloaded control. On the contrary, dynamic compression applied at late time-point not only enhanced the levels of cartilage matrix gene expression, but also suppressed the hypertrophic development of SMSCs compared with unloaded controls. Taken together, our findings suggest that dynamic mechanical compression loading not only promotes chondrogenic differentiation of SMSCs, but also plays a vital role in the maintenance of cartilage phenotype, and our findings also provide an experimental guide for stem cell-based cartilage repair and regeneration.

ZIP8 mediates the extracellular matrix degradation of nucleus pulposus cells via NF-κB signaling pathway.

The extracellular matrix (ECM) degradation of nucleus pulposus cells (NPCs) is mainly induced by metalloproteinases (MMPs). Zn2+ is an essential component of MMPs, but the effect of Zn2+ importers in controlling ECM metabolism remains unclear. The purpose of this research was to identify the involvement of Zn2+ importers in ECM degradation induced by inflammatory stimuli and excessive mechanical stressing. In this study, NPCs from Sprague-Dawley (SD) rats were separated and cultured. FluoZin-3 AM staining was applied to detect [Zn2+]i in NPCs treated with Interleukin-1ß (IL-1ß) or cyclic tensile strain (CTS) with a Flexcell Strain Unit. We found that intracellular Zn2+ concentration ([Zn2+]i) elevated dramatically, and ZIP8 is the predominant Zn2+ importer among all importers in senescent NPCs. The [Zn2+]i and MMP expression level both increased in IL-1ß and CTS treated NPCs. Furthermore, the expression of ZIP8 was also markedly increased. However, knockdown of ZIP8 with siRNA alleviated ECM degradation induced by inflammatory stimuli and CTS. Both stimuli activated NF-κB signaling pathway, and knockdown of ZIP8 effectively inhibited NF-κB signaling pathway activation. In conclusion, knockdown of ZIP8 can alleviate NPCs' ECM degradation caused by inflammatory stimuli and excessive mechanical stressing.

Surface Engineering of Biodegradable Magnesium Alloys for Enhanced Orthopedic Implants.

Magnesium (Mg) alloys have been promised for biomedical implants in orthopedic field, however, the fast corrosion rate and mode challenge their clinical application. To push Mg alloys materials into practice, a composite coating with biodegradable and high compatible components to improve anticorrosion property of an Mg alloy (i.e., AZ31) is designed and fabricated. The inner layer is micro-nano structured Mg(OH)2 through hydrothermal treatment. Then stearic acid (SA) is introduced to modify Mg(OH)2 for better reducing the gap below a surface-degradation polymer layer of poly(1,3-trimethylene carbonate). Benefited by the SA modification effect, this sandwiched coating avoids corrosive medium penetration via enhancing the adhesion strength at the interface between outer and inner layers. Both in vitro and in vivo tests indicate that the composite coating modified AZ31 perform a better anticorrosion behavior and biocompatibility compared to bare AZ31. Strikingly, a 1.7-fold improvement in volume of newly formed bone is observed surrounding the composite coating modified implant after 12 week implantation. The sandwiched biocompatible coating strategy paves a hopeful way for future translational application of Mg alloys orthopedic materials in clinics.

Estrogen prevents articular cartilage destruction in a mouse model of AMPK deficiency via ERK-mTOR pathway.

BACKGROUND: To investigate the mechanism underlying the chondroprotective effect of estrogen in AMP-activated protein kinase (AMPK) deficiency mice. METHODS: Female cartilage-specific AMPKα double knockout (AMPKα cDKO) mice were generated and subjected to ovariectomy (OVX). The model of osteoarthritis (OA) was induced by destabilization of medial meniscus (DMM). Histopathological changes were evaluated by using OARSI scoring systems. Autophagy changes were analyzed by immunofluorescence staining. Human chondrocytes were subjected to mechanical stress to mimic OA development. and incubated in presence of or absence of 17ß-estradiol or/and compound C (AMPK inhibitor) or/and U0126 (ERK inhibitor). The expression levels of ERK1/2 phosphorylation, p70S6K phosphorylation and light chain 3 (LC3) were detected by Western blot. RESULTS: Compared with in OVX-sham AMPKα cDKO and OVX-sham WT mice, DMM-induced OA is more severe, and significantly low level of LC3 was observed in articular cartilage in OVX AMPK cDKO mice. Both mechanical stress and compound C were shown to induce an increase in phosphorylation of p70S6K, respectively. 17ß-estradiol stimulation led to a reduction in the basal level of p70S6K phosphorylation as well as in the compound C or mechanical stress-induced level of p70S6K phosphorylation. 17ß-estradiol stimulation not only led to an increase in LC3 conversion but also overrode the inhibitory effect of compound C on LC3 conversion. The effects of 17ß-estradiol were abrogated by blocking ERK signaling pathway. CONCLUSIONS: Our findings suggest that estrogen can protect articular cartilage from damage during OA development by promoting chondrocyte autophagy via ERK-mammalian target of rapamycin (mTOR) signaling, and give new insight into the mechanism of the chondroprotective effect of estrogen.

Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.

Liver serine-threonine kinase B1 (LKB1) is a tumor suppressor that has been linked to many types of tumors. However, the role of LKB1 in cartilaginous tumorigenesis is still poorly understood. In this study, we find that cartilage-specific, tamoxifen-inducible Lkb1 knockout results in multiple enchondroma-like lesions adjacent to the disorganized growth plates. We showed that chondrocytes retain an immature status caused by loss of Lkb1, which may lead to the dramatic expansion of growth-plate cartilage and the formation of enchondroma-like lesions. Additionally, increased mammalian target of rapamycin complex 1 (mTORC1) activity is observed in the Lkb1 conditional knockout (cKO) chondrocytes, and rapamycin (mTORC1 inhibitor) treatment significantly alleviates the expansion of growth-plate cartilage and eliminates the enchondroma-like lesions in Lkb1 cKO mice. Thus, our findings indicate that loss of Lkb1 leads to the expansion of chondrocytes and the formation of enchondroma-like lesions during postnatal cartilage development, and that the up-regulated mTORC1-signaling pathway is implicated in this process. Our findings suggest that modulation of LKB1 and related signaling is a potential therapy in cartilaginous tumorigenesis.-Zhou, S., Li, Y., Qiao, L., Ge, Y., Huang, X., Gao, X., Ju, H., Wang, W., Zhang, J., Yan, J., Teng, H., Jiang, Q. Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.

Knockdown of Ggps1 in chondrocyte expedites fracture healing by accelerating the progression of endochondral ossification in mice.

Bone fracture healing is achieved through the proliferation and differentiation of stem cells, while bone marrow stem cells (BMSCs) contribute to endochondral ossification. During fracture healing, mesenchymal progenitor cells first form a cartilaginous blastema that becomes vascularized to recruit precursor cells of osteoblasts through the bone morphogenetic protein 2 (Bmp2)/Smad-dependent Runx2 pathway. Statins deplete geranylgeranyl diphosphate (GGPP), which participates in the regulation of BMSCs differentiation, through the inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, leading to impaired protein geranylgeranylation, which strongly impacts the bone synthesis induced by Bmp2. Accordingly, we would like to investigate the role of geranylgeranyl diphosphate synthase 1 (Ggps1) in bone fracture via endochondral ossification in mice. We used a Cre-loxP system, namely the tamoxifen-inducible Collagen 2-CreERT2 Ggps1 fl/fl, to eliminate specifically the Ggps1 activity in chondrocytes of 8-10-week-old mice. We found that the endochondral bone formation, calcification and vasculogenesis of the bony callus were accelerated in fractures in Ggps1-/-mice. Together, the results of this study confirm that the specific deletion of Ggps1, using the Collagen 2-CreERT2 mice, will accelerate the fracture healing process by activating the Bmp2/Smad-dependent Runx2 pathway. In addition, we managed to improve the fracture healing process by inhibiting the Ggps1 activity and its related products with statin drugs.

Accelerated development of instability-induced osteoarthritis in transgenic mice overexpressing SOST.

OBJECTIVE: Sclerostin (SOST), acting as a Wnt antagonist, has been shown to play a key role in regulating bone homestasis, and has also been linked to osteoarthritis (OA) development. Here, we investigated whether overexpressing SOST could affect OA development after destabilization of the medial meniscus (DMM) using SOST transgenic (Tg) mice. METHODS: Bone and cartilage phenotypes of SOST Tg mice at 10 weeks of age were investigated by dual x-ray absorptiometry (DXA) and histology. Subsequently, 10-week-old SOST Tg mice and their wild-type (WT) littermates were subjected to DMM or sham surgery. Knee joints were isolated to evaluate the cartilage damage and the subchondral bone plate thickness at 2 and 8 weeks post-surgery. The changes of chondrocyte anabolic and catabolic responses after IL-1ß or TNFα stimulation, ß-catenin signaling and apoptosis were also measured. RESULTS: Ten-week-old SOST Tg mice were identical to their WT littermate males except that they displayed digit abnormalities and osteopenic, whereas more severe OA was observed in SOST Tg mice at 2 and 8 weeks post-DMM. In addition, DMM resulted in significantly greater subchondral bone changes compared with sham surgery in SOST Tg mice at 8 weeks post-surgery. The accelerated OA in SOST Tg mice may be associated with reduced ß-catenin signaling and increased chondrocyte apoptosis. CONCLUSION: Overexpressing SOST led to accelerated development of instability-induced OA. Our data further highlight that cartilage homeostasis requires finely tuned Wnt signaling.