Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing

Liu, Ran; Jiao, Yu-Rui; Huang, Mei; Zou, Nan-Yu; He, Chen; Huang, Min; Chen, Kai-Xuan; He, Wen-Zhen; Liu, Ling; Sun, Yu-Chen; Xia, Zhu-Ying; Quarles, L. Darryl; Yang, Hai-Lin; Wang, Wei-Shan; Xiao, Zhou-Sheng; Luo, Xiang-Hang; Li, Chang-Jun

doi:10.7150/thno.93269

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Nanotheranostics 2024; 8(4): 442-457. [Abstract] [Full text] [PDF]

Nanotheranostics 2024; 8(4): 427-441. [Abstract] [Full text] [PDF]

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Theranostics 2024; 14(6):2544-2559. doi:10.7150/thno.93269 This issue Cite

Research Paper

Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing

Ran Liu^1#, Yu-Rui Jiao^1#, Mei Huang¹, Nan-Yu Zou¹, Chen He¹, Min Huang¹, Kai-Xuan Chen¹, Wen-Zhen He¹, Ling Liu¹, Yu-Chen Sun¹, Zhu-Ying Xia¹, L. Darryl Quarles², Hai-Lin Yang³, Wei-Shan Wang⁴, Zhou-Sheng Xiao², Xiang-Hang Luo^1,5,6, Chang-Jun Li^1,5,6,7✉

1. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China.
2. Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
3. Department of Orthopaedics, The Second Affiliated Hospital of Fuyang Normal University, Fuyang, Anhui, 236000, China.
4. Department of Orthopaedics, The First Affiliated Hospital of Shihezi University, Shihezi 832061, China.
5. Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
6. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
7. Laboratory Animal Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
# All authors contributed equally

Citation:

Liu R, Jiao YR, Huang M, Zou NY, He C, Huang M, Chen KX, He WZ, Liu L, Sun YC, Xia ZY, Quarles LD, Yang HL, Wang WS, Xiao ZS, Luo XH, Li CJ. Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing. Theranostics 2024; 14(6):2544-2559. doi:10.7150/thno.93269. https://www.thno.org/v14p2544.htm

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Abstract

Background: Mechanical forces are indispensable for bone healing, disruption of which is recognized as a contributing cause to nonunion or delayed union. However, the underlying mechanism of mechanical regulation of fracture healing is elusive.

Methods: We used the lineage-tracing mouse model, conditional knockout depletion mouse model, hindlimb unloading model and single-cell RNA sequencing to analyze the crucial roles of mechanosensitive protein polycystin-1 (PC1, Pkd1) promotes periosteal stem/progenitor cells (PSPCs) osteochondral differentiation in fracture healing.

Results: Our results showed that cathepsin (Ctsk)-positive PSPCs are fracture-responsive and mechanosensitive and can differentiate into osteoblasts and chondrocytes during fracture repair. We found that polycystin-1 declines markedly in PSPCs with mechanical unloading while increasing in response to mechanical stimulus. Mice with conditional depletion of Pkd1 in Ctsk⁺ PSPCs show impaired osteochondrogenesis, reduced cortical bone formation, delayed fracture healing, and diminished responsiveness to mechanical unloading. Mechanistically, PC1 facilitates nuclear translocation of transcriptional coactivator TAZ via PC1 C-terminal tail cleavage, enhancing osteochondral differentiation potential of PSPCs. Pharmacological intervention of the PC1-TAZ axis and promotion of TAZ nuclear translocation using Zinc01442821 enhances fracture healing and alleviates delayed union or nonunion induced by mechanical unloading.

Conclusion: Our study reveals that Ctsk⁺ PSPCs within the callus can sense mechanical forces through the PC1-TAZ axis, targeting which represents great therapeutic potential for delayed fracture union or nonunion.

Keywords: Polycystin-1, Periosteal Stem/Progenitor Cells, Fracture healing, Mechanical stress

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APA

Liu, R., Jiao, Y.R., Huang, M., Zou, N.Y., He, C., Huang, M., Chen, K.X., He, W.Z., Liu, L., Sun, Y.C., Xia, Z.Y., Quarles, L.D., Yang, H.L., Wang, W.S., Xiao, Z.S., Luo, X.H., Li, C.J. (2024). Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing. Theranostics, 14(6), 2544-2559. https://doi.org/10.7150/thno.93269.

ACS

Liu, R.; Jiao, Y.R.; Huang, M.; Zou, N.Y.; He, C.; Huang, M.; Chen, K.X.; He, W.Z.; Liu, L.; Sun, Y.C.; Xia, Z.Y.; Quarles, L.D.; Yang, H.L.; Wang, W.S.; Xiao, Z.S.; Luo, X.H.; Li, C.J. Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing. Theranostics 2024, 14 (6), 2544-2559. DOI: 10.7150/thno.93269.

NLM

CSE

Liu R, Jiao YR, Huang M, Zou NY, He C, Huang M, Chen KX, He WZ, Liu L, Sun YC, Xia ZY, Quarles LD, Yang HL, Wang WS, Xiao ZS, Luo XH, Li CJ. 2024. Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing. Theranostics. 14(6):2544-2559.

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