
CHMP5 蛋白質通過維持細胞內體-溶酶體-線粒體網絡的穩定，抑制骨骼祖細胞衰老，進而調控骨骼形成。


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The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

### Competing Interest Statement

The study started when the corresponding author (X. Ge) worked at the University of Massachusetts Medical School and a previous manuscript related to this study was posted on bioRxiv (https://doi.org/10.1101/2020.08.03.233874). To complete the study for a peer-reviewed publication, the co-first authors and X. Ge generated a novel Chmp5-floxed mouse strain, re-established all animal and cell models in the current laboratory in Beijing, China, and added novel critical experiments to make the conclusion convincing and the study comprehensive. Therefore, we reorganized the data and wrote it as a new paper. All authors agree on the current version of the paper, including its authorship and conclusions. J.H.S. is a scientific co-founder of AAVAA Therapeutics and holds equity in this company but does not have conflicts of interest with this study. Other authors declare no competing interests.

The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence

escrt-蛋白質-chmp5-通過維持內體-溶酶體-線粒體網絡來抑制骨骼祖細胞衰老


ESCRT 蛋白質 CHMP5 通過維持內體-溶酶體-線粒體網絡來抑制骨骼祖細胞衰老


title_rewrite


ESCRT-III 단백질 CHMP5는 VPS4A 단백질을 유지하고 엔도-리소좀 경로를 보존함으로써 골격 전구 세포의 노화를 억제하고, 이는 비정상적인 골 형성을 제한하는 데 중요한 역할을 합니다.


escrt-단백질-chmp5-엔도-리소좀-미토콘드리아-네트워크-보존을-통해-골격-전구-세포-노화-억제


ESCRT 단백질 CHMP5, 엔도-리소좀-미토콘드리아 네트워크 보존을 통해 골격 전구 세포 노화 억제



ESCRT-IIIタンパク質ファミリーのメンバーであるCHMP5は、VPS4Aタンパク質を維持することでエンドリソソーム経路を維持し、骨格前駆細胞の老化を抑制し、骨形成を制御する。


escrtタンパク質chmp5は-エンドリソソーム-ミトコンドリアネットワークを維持することで骨格前駆細胞の老化を抑制する


ESCRTタンパク質CHMP5は、エンドリソソーム-ミトコンドリアネットワークを維持することで骨格前駆細胞の老化を抑制する



CHMP5, an ESCRT-III protein, plays a crucial role in regulating bone formation and skeletal progenitor cell senescence by maintaining the endolysosomal-mitochondrial network.


chmp5-an-escrt-protein-regulates-bone-formation-and-skeletal-progenitor-cell-senescence-via-the-endo-lysosomal-mitochondrial-network


CHMP5, an ESCRT Protein, Regulates Bone Formation and Skeletal Progenitor Cell Senescence via the Endo-Lysosomal-Mitochondrial Network



Osterix (Osx) 在骨細胞中表現，並透過直接調控 Cx43 的轉錄促進細胞間通訊，進而維持骨骼的健康。


Osteocytes, terminal-differentiated cells in bone, are now considered as more pivotal regulators of mature bone homeostasis than other bone cells, since they constitute 90- 95% of the bone cell population. Given their non-migratory nature within the mineralized matrix, their unique dendrites are crucial for cell-to-cell communication in response to both intracellular and extracellular stimuli, such as bone fracture or mechanical load. Here, we showed that Osterix (Osx), usually recognized as a specific doorkeeper for osteoblast differentiation during new bone formation marked by collagen type I α 1 (Col1α1), was unexpectedly co-expressed with Col1α1 in osteocytes within the cortical bone of mice. Deleting Osx in Col1α1-positive osteocytes disrupted cortical bone structure and osteocytic dendrites in mice, thus impairing transcellular fluid flow and intercellular communication. Conversely, overexpression of Osx in osteocytes enhanced these processes. Furthermore, we identified Connexin43, a critical protein of gap junction channel, was a direct transcriptional target of Osx in regulating dendrites of osteocytes. Pharmacological restoration of Connexin43 levels rescued the dysfunction in Osx-deficient osteocytes both in vitro and in vivo. Taken together, this work demonstrated Osx’s distinct role in osteocyte function through maintaining intercellular signaling, which broadened the current understanding of its role in Col1α1-positive bone cells, extending beyond osteoblasts and bone mineralization, offering new insights into bone diseases such as fracture nonunion or disuse osteoporosis.

### Competing Interest Statement

The authors have declared no competing interest.

Osterix Facilitates Osteocytic Communication by Targeting Connexin43

骨細胞中-osterix-透過調控-cx43-表達促進細胞間通訊


骨細胞中 Osterix  透過調控 Cx43 表達促進細胞間通訊



Osterix는 Cx43의 발현을 조절함으로써 골세포의 수지상 돌기 네트워크와 세포 간 소통을 유지하는 데 중요한 역할을 한다.


osterix는-connexin43을-표적으로-하여-골세포-간의-소통을-촉진한다


Osterix는 Connexin43을 표적으로 하여 골세포 간의 소통을 촉진한다



骨細胞におけるOsterixは、コネキシン43を転写標的とすることで、骨細胞間の樹状突起ネットワークとギャップ結合を介した細胞間コミュニケーションの維持に重要な役割を果たしている。


osterixはコネキシン43を標的とすることで骨細胞間のコミュニケーションを促進する


Osterixはコネキシン43を標的とすることで骨細胞間のコミュニケーションを促進する



Osterix, a transcription factor known for its role in osteoblast differentiation, also plays a crucial role in maintaining the osteocyte dendritic network and intercellular communication by directly targeting Connexin43, thereby influencing cortical bone health.


osterix-regulates-osteocyte-communication-and-cortical-bone-health-by-targeting-connexin43


Osterix Regulates Osteocyte Communication and Cortical Bone Health by Targeting Connexin43



Increasing the implant platform and body diameter significantly improves the fatigue life of prosthetic screws in butt-joint implant-supported restorations, while the type of implant-abutment connection (internal or external) has no significant effect.


effect-of-implant-geometry-on-the-fatigue-life-of-prosthetic-screws-in-butt-joint-implant-supported-restorations


Effect of Implant Geometry on the Fatigue Life of Prosthetic Screws in Butt-Joint Implant-Supported Restorations



압연 나사산으로 제조된 보철 나사는 절삭 나사산으로 제조된 나사보다 피로 성능이 우수하여 치과 임플란트 수복물의 수명을 연장할 수 있습니다.


치과-임플란트-수복에-사용되는-보철-나사의-피로-성능-압연-나사산-대-절삭-나사산-비교


치과 임플란트 수복에 사용되는 보철 나사의 피로 성능: 압연 나사산 대 절삭 나사산 비교
