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Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression

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Genes & Diseases 2024年第2期11卷 952-963页

作者： Zhenhao Zhang Doudou Jing Baijun Xuan Zhicai Zhang Wei Wu zengwu shao Department of Orthopedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China Department of Orthopedics The Second Hospital of Shanxi Medical UniversityTaiyuanShanxi 030001China Department of Cardiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430022China

Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tumor progression by metabolic reprogramming.Recent research has shown that methylmalonic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.

关键词： Cellular senescence Elderly patients MAFB-NOTCH3axis Methylmalonic acid Osteosarcoma PI3K-AKTpathway

Corrigendum to"Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression"[Genes&Diseases 11(2024)952-963]

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Genes & Diseases 2024年第3期11卷 491-492页

The authors regret that some data errors were made in"Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression"at Figure 5F for the colony formation of MNNG/HOS cells with si-NOTCH3 and 5G for the tranwell assay of U2OS cells with si-NOCTH3.Correction and supplementation to Figure 5.The author used confusing experimental data and did not notice these errors when submitting the original manuscript.Here,the authors made the latest corrections to the data of the batch of U2OS cells and MNNG/HOS cells transfected with si-NoTCH3.The authors confirm that this correction will not alter the conclusions in the original manuscript.

关键词： PI3K/AKT osteosarcoma submit

Roles of focal adhesion proteins in skeleton and diseases

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Acta Pharmaceutica Sinica B 2023年第3期13卷 998-1013页

作者： Sheng Chen Tailin He Yiming Zhong Mingjue Chen Qing Yao Di Chen zengwu shao Guozhi Xiao Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Biochemistry School of MedicineShenzhen Key Laboratory of Cell MicroenvironmentGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchSouthern University of Science and TechnologyShenzhen 518055China Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

The skeletal system,which contains bones,joints,tendons,ligaments and other elements,plays a wide variety of roles in body shaping,support and movement,protection of internal organs,production of blood cells and regulation of calcium and phosphate metabolism.The prevalence of skeletal diseases and disorders,such as osteoporosis and bone fracture,osteoarthritis,rheumatoid arthritis,and intervertebral disc degeneration,increases with age,causing pain and loss of mobility and creating a huge social and economic burden globally.Focal adhesions(FAs)are macromolecular assemblies that are composed of the extracellular matrix(ECM),integrins,intracellular cytoskeleton and other proteins,including kindlin,talin,vinculin,paxillin,pinch,Src,focal adhesion kinase(FAK)and integrin-linked protein kinase(ILK)and other proteins.FA acts as a mechanical linkage connecting the ECM and cytoskeleton and plays a key role in mediating cell–environment communications and modulates important processes,such as cell attachment,spreading,migration,differentiation and mechanotransduction,in different cells in skeletal system by impacting distinct outside-in and inside-out signaling pathways.This review aims to integrate the up-to-date knowledge of the roles of FA proteins in the health and disease of skeletal system and focuses on the specific molecular mechanisms and underlying therapeutic targets for skeletal diseases.

关键词： Focal adhesion Skeleton Mechanotransduction Signal transduction Integrin Cartilage Intervertebral disc Skeletal diseases

Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc

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Bone Research 2022年第1期10卷 165-177页

作者： Sheng Chen Xiaohao Wu Yumei Lai Di Chen Xiaochun Bai Sheng Liu Yongchao Wu Mingjue Chen Yuxiao Lai Huiling Cao zengwu shao Guozhi Xiao Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Biochemistry School of MedicineSouthern University of Science and TechnologyGuangdong Provincial Key Laboratory of Cell Microenvironment and Disease ResearchShenzhen Key Laboratory of Cell MicroenvironmentShenzhen 518055China Department of Orthopedic Surgery Rush University Medical CenterChicagoIL 60612USA Research Center for Human Tissues and Organs Degeneration Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Department of Cell Biology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Centre for Translational Medicine Research and Development Institute of Biomedical and Health EngineeringShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Intervertebral disc(IVD) degeneration(IVDD) is the main cause of low back pain with major social and economic burdens;however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus(NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix(ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.

关键词： Kindlin homeostasis prevention

Characterizing the tumor microenvironment at the single-cell level reveals a novel immune evasion mechanism in osteosarcoma

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Bone Research 2023年第1期11卷 124-135页

作者： Weijian Liu Hongzhi Hu zengwu shao Xiao Lv Zhicai Zhang Xiangtian Deng Qingcheng Song Yong Han Tao Guo Liming Xiong Baichuan Wang Yingze Zhang Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Department of Orthopaedic Surgery The Third Hospital of Hebei Medical UniversityShijiazhuang050051China Orthopaedic Institute of Hebei Province Shijiazhuang050051China Key Laboratory of Biomechanics of Hebei Province Shijiazhuang050051China Animal Center of Hebei Ex&In vivo Biotechnology Shijiazhuang050051China Department of Pharmacy Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina Department of Pathology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

The immune microenvironment extensively participates in tumorigenesis as well as progression in osteosarcoma(OS).However,the landscape and dynamics of immune cells in OS are poorly characterized.By analyzing single-cell RNA sequencing(sc RNA-seq)data,which characterize the transcription state at single-cell resolution,we produced an atlas of the immune microenvironment in OS.The results suggested that a cluster of regulatory dendritic cells(DCs)might shape the immunosuppressive microenvironment in OS by recruiting regulatory T cells.We also found that major histocompatibility complex class I(MHC-I)molecules were downregulated in cancer cells.The findings indicated a reduction in tumor immunogenicity in OS,which can be a potential mechanism of tumor immune escape.Of note,CD24 was identified as a novel“don’t eat me”signal that contributed to the immune evasion of OS cells.Altogether,our findings provide insights into the immune landscape of OS,suggesting that myeloid-targeted immunotherapy could be a promising approach to treat OS.

关键词： osteosarcoma microenvironment CD24

Three-dimensional-printed titanium prostheses with bone trabeculae enable mechanical-biological reconstruction after resection of bone tumours

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Biomaterials Translational 2022年第2期3卷 134-141页

作者： Feifei Pu Wei Wu Doudou Jing Yihan Yu Yizhong Peng Jianxiang Liu Qiang Wu Baichuan Wang Zhicai Zhang zengwu shao Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Reconstruction after resection has always been an urgent problem in the treatment of bone tumours.There are many methods that can be used to reconstruct bone defects;however,there are also many complications,and it is difficult to develop a safe and effective reconstruction plan for the treatment of bone tumours.With the rapid development of digital orthopaedics,three-dimensional printing technology can solve this problem.The three-dimensional printing of personalised prostheses has many advantages.It can be used to print complex structures that are difficult to fabricate using traditional processes and overcome the problems of stress shielding and low biological activity of conventional prostheses.In this study,12 patients with bone tumours were selected as research subjects,and based on individualised reverse-engineering design technology,a three-dimensional model of each prosthesis was designed and installed using medical image data.Ti6Al4V was used as the raw material to prepare the prostheses,which were used to repair bone defects after surgical resection.The operation time was 266.43±21.08 minutes(range 180-390 minutes),and intraoperative blood loss was 857.26±84.28 mL(range 800-2500 mL).One patient had delayed wound healing after surgery,but all patients survived without local tumour recurrence,and no tumour metastasis was found.No aseptic loosening or structural fracture of the prosthesis,and no non-mechanical prosthesis failure caused by infection,tumour recurrence,or progression was observed.The Musculo-Skeletal Tumour Society(MSTS)score of limb function was 22.53±2.09(range 16-26),and ten of the 12 patients scored≥20 and were able to function normally.The results showed that three-dimensional printed prostheses with an individualised design can achieve satisfactory short-term clinical efficacy in the reconstruction of large bone defects after bone tumour resection.

关键词： bone defect bone tumour printed biomechanical reconstruction prostheses three-dimensional

Development of porphyrin and titanium dioxide sonosensitizers for sonodynamic cancer therapy

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Biomaterials Translational 2021年第1期2卷 72-85页

作者： Xiangyu Deng zengwu shao Yanli Zhao Department of Orthopaedic Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina Division of Chemistry and Biological Chemistry School of Physical and Mathematical SciencesNanyang Technological UniversitySingapore

Sonodynamic therapy for malignant tumours has gained much attention for its deep penetration effect and efficient tumour killing ability.The design,modification,and utilization of sonosensitizers are important aspects of sonodynamic therapy.As an essential factor in this process,highly effective sonosensitizers should be developed to facilitate the clinical applications of sonodynamic therapy.This review takes porphyrin-and titanium dioxide(TiO_(2))-based systems as representative organic and inorganic sonosensitizers respectively,and summarizes their characteristics and biological effects as sonodynamic therapy.Upon discovery of novel sonosensitizers,sonodynamic therapy becomes an efficient means of adjuvant therapy for the treatment of malignant tumours.

关键词： cancer treatment porphyrins sonodynamic therapy sonosensitizers TiO_(2)

Engineered microorganisms-based delivery systems for targeted cancer therapy:a narrative review

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Biomaterials Translational 2022年第3期3卷 201-212页

作者： Xin Huang Haoyu Guo Lutong Wang zengwu shao Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Microorganisms with innate and artificial advantages have been regarded as intelligent drug delivery systems for cancer therapy with the help of engineering technology.Although numerous studies have confirmed the promising prospects of microorganisms in cancer,several problems such as immunogenicity and toxicity should be addressed before further clinical applications.This review aims to investigate the developments of engineered microorganisms-based delivery systems for targeted cancer therapy.The main types and characteristics of microorganisms such as bacteria,viruses,fungi,microalgae,and their components are introduced in detail.Moreover,the engineering strategies and biomaterials design of microorganisms are further discussed.Most importantly,we discussed the innovative attempts and therapeutic effects of engineered microorganisms in cancer.Taken together,engineered microorganisms-based delivery systems hold tremendous prospects for biomedical applications in targeted cancer therapy.

关键词： drug delivery systems engineering strategies microorganisms targeted cancer therapy

Traumatic brain injury stimulates sympathetic tone-mediated bone marrow myelopoiesis to favor fracture healing

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Signal Transduction and Targeted Therapy 2023年第8期8卷 3751-3767页

作者： Weijian Liu Wei Chen Mao Xie Chao Chen zengwu shao Yiran Zhang Haiyue Zhao Qingcheng Song Hongzhi Hu Xin Xing Xianyi Cai Xiangtian Deng Xinyan Li Peng Wang Guohui Liu Liming Xiong Xiao Lv Yingze Zhang Department of Orthopaedics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Orthopaedic Surgery The Third Hospital of Hebei Medical UniversityShijiazhuang 050051China School of Medicine Nankai UniversityTianjin 300071China NHC Key Laboratory of Intelligent Orthopeadic Equipment Third Hospital of Hebei Medical UniversityShijiazhuang 050051China Animal Center of Hebei Ex&In vivo Biotechnology Shijiazhuang 050051China Department of Physiology School of Basic Medicine and Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Traumatic brain injury(TBI)accelerates fracture healing,but the underlying mechanism remains largely unknown.Accumulating evidence indicates that the central nervous system(CNS)plays a pivotal role in regulating immune system and skeletal homeostasis.However,the impact of CNS injury on hematopoiesis commitment was overlooked.Here,we found that the dramatically elevated sympathetic tone accompanied with TBI-accelerated fracture healing;chemical sympathectomy blocks TBIinduced fracture healing.TBI-induced hypersensitivity of adrenergic signaling promotes the proliferation of bone marrow hematopoietic stem cells(HSCs)and swiftly skews HSCs toward anti-inflammation myeloid cells within 14 days,which favor fracture healing.Knockout ofβ3-orβ2-adrenergic receptor(AR)eliminate TBI-mediated anti-inflammation macrophage expansion and TBIaccelerated fracture healing.RNA sequencing of bone marrow cells revealed that Adrb2 and Adrb3 maintain proliferation and commitment of immune cells.Importantly,flow cytometry confirmed that deletion ofβ2-AR inhibits M2 polarization of macrophages at 7th day and 14th day;and TBI-induced HSCs proliferation was impaired inβ3-AR knockout mice.Moreover,β3-andβ2-AR agonists synergistically promote infiltration of M2 macrophages in callus and accelerate bone healing process.Thus,we conclude that TBI accelerates bone formation during early stage of fracture healing process by shaping the anti-inflammation environment in the bone marrow.These results implicate that the adrenergic signals could serve as potential targets for fracture management.

关键词： healing inflammation Traumatic