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Signaling pathway mechanisms of circadian clock gene Bmal1 regulating bone and cartilage metabolism: a review
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-27 DOI: 10.1038/s41413-025-00403-6
Yiting Ze, Yongyao Wu, Zhen Tan, Rui Li, Rong Li, Wenzhen Gao, Qing Zhao

Circadian rhythm is ubiquitous in nature. Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network, and regulate a variety of physiological and pathological processes, including bone and cartilage metabolism. Deletion of the core clock gene Bmal1 leads to pathological bone alterations, while the phenotypes are not consistent. Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism, but the exact regulatory mechanisms remain unclear. This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism, the upstream regulatory factors that control Bmal1, and the current Bmal1 knockout mouse models for research. We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.

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引用次数: 0
Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis 异维菌素以SIRT3为靶点,通过调节有丝分裂介导的铁蛋白沉积,预防类固醇诱发的股骨头坏死
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-26 DOI: 10.1038/s41413-024-00390-0
Yinuo Fan, Zhiwen Chen, Haixing Wang, Mengyu Jiang, Hongduo Lu, Yangwenxiang Wei, Yunhao Hu, Liang Mo, Yuhao Liu, Chi Zhou, Wei He, Zhenqiu Chen

The death of osteoblasts induced by glucocorticoid (GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head (SIONFH). Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH. Isovitexin has demonstrated antioxidant properties, but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored. In this study, we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches. We found an imbalance in mitochondrial homeostasis and ferroptosis-induced impairment of osteogenic capacity in SIONFH. Subsequently, we investigated the cause-and-effect relationship between mitochondria and ferroptosis, as well as the regulatory role of mitophagy in maintaining mitochondrial homeostasis and controlling ferroptosis. We then identified the critical involvement of SIRT3 in modulating mitochondrial homeostasis and ferroptosis. Furthermore, molecular docking and co-immunoprecipitation confirmed the strong interaction between SIRT3 and BNIP3. Strikingly, restoring SIRT3 expression significantly inhibited pathological mitophagy mediated by the BNIP3/NIX pathway. Additionally, we discovered that Isovitexin, by promoting SIRT3 expression, effectively regulated mitophagy, preserved mitochondrial homeostasis in osteoblasts, suppressed ferroptosis, and restored osteogenic capacity, leading to remarkable improvements in SIONFH. These findings reveal the effects and molecular mechanisms of Isovitexin on SIONFH and highlight the potential of targeting SIRT3 as a promising strategy to suppress mitophagy-mediated ferroptosis in osteoblasts and against SIONFH.

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引用次数: 0
Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-26 DOI: 10.1038/s41413-024-00393-x
Mohammad Alhashmi, Abdulrahman M. E. Gremida, Santosh K. Maharana, Marco Antonaci, Amy Kerr, Shijian Fu, Sharna Lunn, David A. Turner, Noor A. Al-Maslamani, Ke Liu, Maria M. Meschis, Hazel Sutherland, Peter Wilson, Peter Clegg, Grant N. Wheeler, Robert J. van ‘t Hof, George Bou-Gharios, Kazuhiro Yamamoto

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards, especially in the perichondrium, the stem cell layer surrounding developing limbs essential for bone formation. Lrp1 deficiency in these stem cells causes joint fusion, malformation of cartilage/bone template and markedly delayed or lack of primary ossification. These abnormalities, which resemble phenotypes associated with Wnt signalling pathways, result in severe and persistent skeletal defects including a severe deficit in hip joint and patella, and markedly deformed and low-density long bones leading to dwarfism and impaired mobility. Mechanistically, we show that LRP1 regulates core non-canonical Wnt/planar cell polarity (PCP) components that may explain the malformation of long bones. LRP1 directly binds to Wnt5a, facilitates its cell-association and endocytic degradation and recycling. In the developing limbs, LRP1 partially colocalises with Wnt5a and its deficiency alters abundance and distribution of Wnt5a and Vangl2. Finally, using Xenopus as a model system, we show the regulatory role for LRP1 in Wnt/PCP signalling. We propose that in skeletal progenitors, LRP1 plays a critical role in formation and maturity of multiple bones and joints by regulating Wnt signalling, providing novel insights into the fundamental processes of morphogenesis and the emergence of skeletal pathologies.

{"title":"Skeletal progenitor LRP1 deficiency causes severe and persistent skeletal defects with Wnt pathway dysregulation","authors":"Mohammad Alhashmi, Abdulrahman M. E. Gremida, Santosh K. Maharana, Marco Antonaci, Amy Kerr, Shijian Fu, Sharna Lunn, David A. Turner, Noor A. Al-Maslamani, Ke Liu, Maria M. Meschis, Hazel Sutherland, Peter Wilson, Peter Clegg, Grant N. Wheeler, Robert J. van ‘t Hof, George Bou-Gharios, Kazuhiro Yamamoto","doi":"10.1038/s41413-024-00393-x","DOIUrl":"https://doi.org/10.1038/s41413-024-00393-x","url":null,"abstract":"<p>Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E10.5 and onwards, especially in the perichondrium, the stem cell layer surrounding developing limbs essential for bone formation. <i>Lrp1</i> deficiency in these stem cells causes joint fusion, malformation of cartilage/bone template and markedly delayed or lack of primary ossification. These abnormalities, which resemble phenotypes associated with Wnt signalling pathways, result in severe and persistent skeletal defects including a severe deficit in hip joint and patella, and markedly deformed and low-density long bones leading to dwarfism and impaired mobility. Mechanistically, we show that LRP1 regulates core non-canonical Wnt/planar cell polarity (PCP) components that may explain the malformation of long bones. LRP1 directly binds to Wnt5a, facilitates its cell-association and endocytic degradation and recycling. In the developing limbs, LRP1 partially colocalises with Wnt5a and its deficiency alters abundance and distribution of Wnt5a and Vangl2. Finally, using <i>Xenopus</i> as a model system, we show the regulatory role for LRP1 in Wnt/PCP signalling. We propose that in skeletal progenitors, LRP1 plays a critical role in formation and maturity of multiple bones and joints by regulating Wnt signalling, providing novel insights into the fundamental processes of morphogenesis and the emergence of skeletal pathologies.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"47 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Enhancer-driven Shh signaling promotes glia-to-mesenchyme transition during bone repair
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-26 DOI: 10.1038/s41413-024-00396-8
Xin Shen, Hang Zhang, Zesheng Song, Yangjiele Dong, Xiao Ge, Shenghao Jin, Songsong Guo, Ping Zhang, Yu Fu, Yuchi Zhu, Na Xiao, Dongmiao Wang, Jie Cheng, Rongyao Xu, Hongbing Jiang

Plp1-lineage Schwann cells (SCs) of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing, and the abnormal plasticity of SCs would jeopardize the bone regeneration. However, how Plp1-lineage cells respond to injury and initiate the vascularized osteogenesis remains incompletely understood. Here, by employing single-cell transcriptional profiling combined with lineage-specific tracing models, we uncover that Plp1-lineage cells undergoing injury-induced glia-to-MSCs transition contributed to osteogenesis and revascularization in the initial stage of bone injury. Importantly, our data demonstrated that the Sonic hedgehog (Shh) signaling was responsible for the transition process initiation, which was strongly activated by c-Jun/SIRT6/BAF170 complex-driven Shh enhancers. Collectively, these findings depict an injury-specific niche signal-mediated Plp1-lineage cells transition towards Gli1+ MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.

{"title":"Enhancer-driven Shh signaling promotes glia-to-mesenchyme transition during bone repair","authors":"Xin Shen, Hang Zhang, Zesheng Song, Yangjiele Dong, Xiao Ge, Shenghao Jin, Songsong Guo, Ping Zhang, Yu Fu, Yuchi Zhu, Na Xiao, Dongmiao Wang, Jie Cheng, Rongyao Xu, Hongbing Jiang","doi":"10.1038/s41413-024-00396-8","DOIUrl":"https://doi.org/10.1038/s41413-024-00396-8","url":null,"abstract":"<p>Plp1-lineage Schwann cells (SCs) of peripheral nerve play a critical role in vascular remodeling and osteogenic differentiation during the early stage of bone healing, and the abnormal plasticity of SCs would jeopardize the bone regeneration. However, how Plp1-lineage cells respond to injury and initiate the vascularized osteogenesis remains incompletely understood. Here, by employing single-cell transcriptional profiling combined with lineage-specific tracing models, we uncover that Plp1-lineage cells undergoing injury-induced glia-to-MSCs transition contributed to osteogenesis and revascularization in the initial stage of bone injury. Importantly, our data demonstrated that the Sonic hedgehog (Shh) signaling was responsible for the transition process initiation, which was strongly activated by c-Jun/SIRT6/BAF170 complex-driven <i>Shh</i> enhancers. Collectively, these findings depict an injury-specific niche signal-mediated Plp1-lineage cells transition towards Gli1<sup>+</sup> MSCs and may be instructive for approaches to promote bone regeneration during aging or other bone diseases.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":"16 1","pages":""},"PeriodicalIF":12.7,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Skeletal abnormalities caused by a Connexin43R239Q mutation in a mouse model for autosomal recessive craniometaphyseal dysplasia 常染色体隐性颅骨干骺端发育不良小鼠模型中Connexin43R239Q突变引起的骨骼异常
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-23 DOI: 10.1038/s41413-024-00383-z
Yasuyuki Fujii, Iichiro Okabe, Ayano Hatori, Shyam Kishor Sah, Jitendra Kanaujiya, Melanie Fisher, Rachael Norris, Mark Terasaki, Ernst J. Reichenberger, I-Ping Chen

Craniometaphyseal dysplasia (CMD), a rare craniotubular disorder, occurs in an autosomal dominant (AD) or autosomal recessive (AR) form. CMD is characterized by hyperostosis of craniofacial bones and metaphyseal flaring of long bones. Many patients with CMD suffer from neurological symptoms. The pathogenesis of CMD is not fully understood. Treatment is limited to craniofacial surgery. Here, we report a knock in (KI) mouse model for AR CMD carrying a Cx43R239Q mutation. Cx43KI/KI mice replicate typical features of AR CMD, including thickening of craniofacial bones, club-shaped femurs, and widened diaphyseal cortical bones. Female Cx43KI/KI mice display remarkably more bone overgrowth than male Cx43KI/KI mice as they age. In contrast to Cx43+/+ littermates, Cx43KI/KI mice exhibit periosteal bone deposition and increased osteoclast (OC) numbers in the endosteum of long bones. Although formation of resting OCs in Cx43+/+ and Cx43KI/KI mice is comparable, the actively resorbing Cx43KI/KI OCs have reduced resorption on bone chips. Cx43KI/KI mice display reduced osteocyte dendrites. RNA from Cx43KI/KI femoral cortical bones show reduced expression levels of Sost, Tnf-α, IL-1β, Esr1, Esr2, and a lower Rankl/Opg ratio. Moreover, the Cx43R239Q mutation results in altered spatial expression of Cx43 protein and mild reduction of gap junction and hemichannel activity. The distinct phenotype seen in Cx43KI/KI mice but not in Cx43 ablation models suggests that Cx43 loss-of-function is unlikely the main cause of AR CMD. Additional studies are required to investigate new roles of CMD-mutant Cx43.

颅干骺端发育不良(CMD)是一种罕见的颅管疾病,常染色体显性遗传(AD)或常染色体隐性遗传(AR)。CMD的特征是颅面骨肥厚和长骨干骺端突出。许多CMD患者都有神经系统症状。CMD的发病机制尚不完全清楚。治疗仅限于颅面手术。在这里,我们报告了一个携带Cx43R239Q突变的AR CMD敲入(KI)小鼠模型。Cx43KI/KI小鼠复制了AR CMD的典型特征,包括颅面骨增厚、棒状股骨和骨干皮质骨增宽。随着年龄的增长,雌性Cx43KI/KI小鼠比雄性Cx43KI/KI小鼠表现出明显更多的骨过度生长。与Cx43+/+窝鼠相比,Cx43KI/KI小鼠表现出骨膜骨沉积和长骨内膜破骨细胞(OC)数量增加。虽然Cx43+/+和Cx43KI/KI小鼠的静息oc的形成是相似的,但主动吸收Cx43KI/KI的oc减少了骨片的吸收。Cx43KI/KI小鼠显示骨细胞树突减少。Cx43KI/KI股骨皮质骨的RNA显示Sost、Tnf-α、IL-1β、Esr1、Esr2的表达水平降低,Rankl/Opg比值降低。此外,Cx43R239Q突变导致Cx43蛋白的空间表达改变,间隙连接和半通道活性轻度降低。在Cx43KI/KI小鼠中观察到的不同表型,而在Cx43消融模型中没有发现,这表明Cx43功能丧失不太可能是AR CMD的主要原因。需要进一步的研究来研究cmd突变体Cx43的新作用。
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引用次数: 0
Role of macrophage in intervertebral disc degeneration 巨噬细胞在椎间盘退变中的作用
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-23 DOI: 10.1038/s41413-024-00397-7
Yiming Dou, Yiming Zhang, Yang Liu, Xun Sun, Xinyu Liu, Bin Li, Qiang Yang

Intervertebral disc degeneration is a degenerative disease where inflammation and immune responses play significant roles. Macrophages, as key immune cells, critically regulate inflammation through polarization into different phenotypes. In recent years, the role of macrophages in inflammation-related degenerative diseases, such as intervertebral disc degeneration, has been increasingly recognized. Macrophages construct the inflammatory microenvironment of the intervertebral disc and are involved in regulating intervertebral disc cell activities, extracellular matrix metabolism, intervertebral disc vascularization, and innervation, profoundly influencing the progression of disc degeneration. To gain a deeper understanding of the inflammatory microenvironment of intervertebral disc degeneration, this review will summarize the role of macrophages in the pathological process of intervertebral disc degeneration, analyze the regulatory mechanisms involving macrophages, and review therapeutic strategies targeting macrophage modulation for the treatment of intervertebral disc degeneration. These insights will be valuable for the treatment and research directions of intervertebral disc degeneration.

椎间盘退变是一种退行性疾病,炎症和免疫反应起重要作用。巨噬细胞作为关键的免疫细胞,通过分化成不同的表型来关键地调节炎症。近年来,巨噬细胞在炎症相关退行性疾病(如椎间盘退变)中的作用被越来越多地认识到。巨噬细胞构建椎间盘炎症微环境,参与调节椎间盘细胞活动、细胞外基质代谢、椎间盘血管化和神经支配,深刻影响椎间盘退变的进展。为了更深入地了解椎间盘退变的炎症微环境,本文将总结巨噬细胞在椎间盘退变病理过程中的作用,分析巨噬细胞参与的调控机制,并综述针对巨噬细胞调节治疗椎间盘退变的治疗策略。这些见解将为椎间盘退变的治疗和研究方向提供参考。
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引用次数: 0
FGFR antagonists restore defective mandibular bone repair in a mouse model of osteochondrodysplasia FGFR拮抗剂在骨软骨发育不良小鼠模型中恢复下颌骨修复缺陷
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-21 DOI: 10.1038/s41413-024-00385-x
Anne Morice, Amélie de La Seiglière, Alexia Kany, Roman H. Khonsari, Morad Bensidhoum, Maria-Emilia Puig-Lombardi, Laurence Legeai Mallet

Gain-of-function mutations in fibroblast growth factor receptor (FGFR) genes lead to chondrodysplasia and craniosynostoses. FGFR signaling has a key role in the formation and repair of the craniofacial skeleton. Here, we analyzed the impact of Fgfr2- and Fgfr3-activating mutations on mandibular bone formation and endochondral bone repair after non-stabilized mandibular fractures in mouse models of Crouzon syndrome (Crz) and hypochondroplasia (Hch). Bone mineralization of the calluses was abnormally high in Crz mice and abnormally low in Hch mice. The latter model presented pseudarthrosis and impaired chondrocyte differentiation. Spatial transcriptomic analyses of the Hch callus revealed abnormally low expression of Col11, Col1a, Dmp1 genes in mature chondrocytes. We found that the expression of genes involved in autophagy and apoptosis (Smad1, Comp, Birc2) was significantly perturbed and that the Dusp3, Dusp9, and Socs3 genes controlling the mitogen-activated protein kinase pathway were overexpressed. Lastly, we found that treatment with a tyrosine kinase inhibitor (BGJ398, infigratinib) or a C-type natriuretic peptide (BMN111, vosoritide) fully rescued the defective endochondral bone repair observed in Hch mice. Taken as a whole, our findings show that FGFR3 is a critical orchestrator of bone repair and provide a rationale for the development of potential treatments for patients with FGFR3-osteochondrodysplasia.

成纤维细胞生长因子受体(FGFR)基因的功能获得性突变可导致软骨发育不良和颅缝紧闭。FGFR信号在颅面骨骼的形成和修复中起关键作用。在这里,我们分析了Fgfr2-和fgfr3激活突变对Crouzon综合征(Crz)和软骨发育不全(Hch)小鼠下颌非稳定骨折后下颌骨形成和软骨内骨修复的影响。Crz小鼠的骨矿化异常高,Hch小鼠的骨矿化异常低。后一种模型出现假关节,软骨细胞分化受损。Hch愈伤组织的空间转录组学分析显示,成熟软骨细胞中Col11、Col1a、Dmp1基因的表达异常低。我们发现参与自噬和凋亡的基因(Smad1, Comp, Birc2)的表达明显受到干扰,而控制丝裂原活化蛋白激酶途径的基因Dusp3, Dusp9和Socs3的表达过度。最后,我们发现酪氨酸激酶抑制剂(BGJ398, infigratinib)或c型利钠肽(BMN111, vosoritide)完全恢复了Hch小鼠软骨内骨修复的缺陷。总的来说,我们的研究结果表明FGFR3是骨修复的关键协调者,并为FGFR3-骨软骨发育不良患者的潜在治疗方法的开发提供了理论依据。
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引用次数: 0
GnIH secreted by green light exposure, regulates bone mass through the activation of Gpr147 GnIH由绿光照射分泌,通过激活Gpr147调节骨量
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-21 DOI: 10.1038/s41413-024-00389-7
Yu You, Konglin Huo, Liang He, Tongyue Wang, Lei Zhao, Rong Li, Xiaoqing Cheng, Xuebin Ma, Zhiying Yue, Stefan Siwko, Ning Wang, Lujian Liao, Mingyao Liu, Jian Luo

Reproductive hormones associated with the hypothalamic-pituitary-gonadal (HPG) axis are closely linked to bone homeostasis. In this study, we demonstrate that Gonadotropin inhibitory hormone (GnIH, one of the key reproductive hormones upstream of the HPG axis) plays an indispensable role in regulating bone homeostasis and maintaining bone mass. We find that deficiency of GnIH or its receptor Gpr147 leads to a significant reduction in bone mineral density (BMD) in mice primarily by enhancement of osteoclast activation in vivo and in vitro. Mechanistically, GnIH/Gpr147 inhibits osteoclastogenesis by the PI3K/AKT, MAPK, NF-κB and Nfatc1 signaling pathways. Furthermore, GnIH treatment was able to alleviate bone loss in aging, ovariectomy (OVX) or LPS-induced mice. Moreover, the therapy using green light promotes the release of GnIH and rescues OVX-induced bone loss. In humans, serum GnIH increases and bone resorption markers decrease after green light exposure. Therefore, our study elucidates that GnIH plays an important role in maintaining bone homeostasis via modulating osteoclast differentiation and demonstrates the potential of GnIH therapy or green light therapy in preventing osteoporosis.

与下丘脑-垂体-性腺(HPG)轴相关的生殖激素与骨稳态密切相关。在本研究中,我们证明了促性腺激素抑制激素(GnIH)是HPG轴上游的关键生殖激素之一,在调节骨稳态和维持骨量中起着不可或缺的作用。我们发现GnIH或其受体Gpr147的缺乏主要通过增强体内和体外破骨细胞激活导致小鼠骨矿物质密度(BMD)的显著降低。机制上,GnIH/Gpr147通过PI3K/AKT、MAPK、NF-κB和Nfatc1信号通路抑制破骨细胞生成。此外,GnIH治疗能够减轻衰老、卵巢切除术(OVX)或脂多糖诱导小鼠的骨质流失。此外,使用绿光的治疗促进GnIH的释放,挽救ovx诱导的骨质流失。在人类中,在绿光照射后,血清GnIH升高,骨吸收标志物降低。因此,我们的研究阐明了GnIH通过调节破骨细胞分化在维持骨稳态中发挥重要作用,并证明了GnIH治疗或绿光治疗在预防骨质疏松症中的潜力。
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引用次数: 0
Polycystin-1 regulates tendon-derived mesenchymal stem cells fate and matrix organization in heterotopic ossification 多囊蛋白-1调控异位骨化过程中肌腱源性间充质干细胞的命运和基质组织
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-20 DOI: 10.1038/s41413-024-00392-y
Yi Li Xu, Mei Huang, Yang Zhang, Xin Ying Su, Min Huang, Nan Yu Zou, Yu Rui Jiao, Yu Chen Sun, Ling Liu, Yong Hua Lei, Chang Jun Li

Mechanical stress modulates bone formation and organization of the extracellular matrix (ECM), the interaction of which affects heterotopic ossification (HO). However, the mechanically sensitive cell populations in HO and the underlying mechanism remain elusive. Here, we show that the mechanical protein Polysyctin-1 (PC1, Pkd1) regulates CTSK lineage tendon-derived mesenchymal stem cell (TDMSC) fate and ECM organization, thus affecting HO progression. First, we revealed that CTSK lineage TDMSCs are the major source of osteoblasts and fibroblasts in HO and are responsive to mechanical cues via single-cell RNA sequencing analysis and experiments with a lineage tracing mouse model. Moreover, we showed that PC1 mediates the mechanosignal transduction of CTSK lineage TDMSCs to regulate osteogenic and fibrogenic differentiation and alters the ECM architecture by facilitating TAZ nuclear translocation. Conditional gene depletion of Pkd1 or Taz in CTSK lineage cells and pharmaceutical intervention in the PC1-TAZ axis disrupt osteogenesis, fibrogenesis and ECM organization, and consequently attenuate HO progression. These findings suggest that mechanically sensitive CTSK-lineage TDMSCs contribute to heterotopic ossification through PC1-TAZ signaling axis mediated cell fate determination and ECM organization.

机械应力调节骨形成和细胞外基质(ECM)的组织,两者的相互作用影响异位骨化(HO)。然而,HO的机械敏感细胞群和潜在的机制仍然是难以捉摸的。在这里,我们发现机械蛋白Polysyctin-1 (PC1, Pkd1)调节CTSK谱系肌腱源性间充质干细胞(TDMSC)的命运和ECM组织,从而影响HO的进展。首先,我们通过单细胞RNA测序分析和谱系追踪小鼠模型实验发现,CTSK谱系TDMSCs是HO中成骨细胞和成纤维细胞的主要来源,并且对机械信号有反应。此外,我们发现PC1介导CTSK谱系TDMSCs的机械信号转导,调节成骨和纤维化分化,并通过促进TAZ核易位改变ECM结构。CTSK谱系细胞中Pkd1或Taz的条件性基因缺失和PC1-TAZ轴的药物干预会破坏成骨、纤维发生和ECM组织,从而减弱HO的进展。这些发现表明,机械敏感的ctsk谱系TDMSCs通过PC1-TAZ信号轴介导的细胞命运决定和ECM组织促进异位骨化。
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引用次数: 0
Fibrocyte enrichment and myofibroblastic adaptation causes nucleus pulposus fibrosis and associates with disc degeneration severity 纤维细胞富集和肌成纤维细胞适应导致髓核纤维化并与椎间盘退变严重程度相关
IF 12.7 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-01-20 DOI: 10.1038/s41413-024-00372-2
Yi Sun, Yan Peng, Zezhuo Su, K. H. Kyle So, Qiuji Lu, Maojiang Lyu, Jianwei Zuo, Yongcan Huang, Zhiping Guan, Kenneth M. C. Cheung, Zhaomin Zheng, Xintao Zhang, Victor Y. L. Leung

Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergence of fibroblastic cells in disc degeneration has been reported, yet their nature and origin remain elusive. In this study, we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens. We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype, characterized by CD45 and collagen I dual positivity, and expression of myofibroblast marker α-smooth muscle actin. Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells - and immunocytes-clusters, expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β. In injury-induced mouse disc degeneration model, fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype. Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs, and prevent disc height loss and histomorphological abnormalities. Marker analysis supports that disc degeneration progression is dependent on a function of CD45+COL1A1+ and αSMA+ cells. Our findings reveal that myeloid-derived fibrocytes play a pivotal role in NP fibrosis and may therefore be a target for modifying disc degeneration and promoting its repair.

髓核(NP)纤维化重塑导致椎间盘结构和力学异常,易发生退变,导致腰痛的发生和残疾。椎间盘退变中纤维母细胞的出现已有报道,但其性质和起源仍不清楚。在这项研究中,我们对多个单细胞RNA测序数据集进行了综合分析,以询问退行性人类NP标本中的细胞异质性和成纤维细胞样实体。我们发现椎间盘退变的严重程度与纤维细胞表型的富集有关,其特征是CD45和胶原I双重阳性,以及肌成纤维细胞标志物α-平滑肌肌动蛋白的表达。精细的聚类和分类将纤维细胞样群体区分为NP细胞群和免疫细胞群中的亚型,表达椎间盘退变标志物HTRA1和ANGPTL4以及与TGF-β反应相关的基因。在损伤性小鼠椎间盘退变模型中,纤维细胞被募集到NP中纤维化,呈肌成纤维细胞表型。白喉毒素消融骨髓来源谱系的CD11b-DTR小鼠的纤维细胞可明显减弱退变椎间盘NP中的纤维模型和肌成纤维细胞的形成,防止椎间盘高度下降和组织形态学异常。标记分析支持椎间盘退变的进展依赖于CD45+COL1A1+和αSMA+细胞的功能。我们的研究结果表明,髓源性纤维细胞在NP纤维化中起关键作用,因此可能是改变椎间盘退变和促进其修复的靶点。
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引用次数: 0
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