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Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification.
J Clin Invest. 2020 12 01; 130(12):6354-6365.JCI

Abstract

Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk+Scx+ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.

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Authors+Show Affiliations

Feng H
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Xing W
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Han Y
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Sun J
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Kong M
Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
Gao B
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Yang Y
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Yin Z
Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China.
Chen X
Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China.
Zhao Y
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Bi Q
Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
Zou W
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

MeSH

AnimalsBasic Helix-Loop-Helix Transcription FactorsCathepsin KGene Expression Regulation, EnzymologicHedgehog ProteinsMiceMice, TransgenicOssification, HeterotopicRepressor ProteinsSignal TransductionStem CellsTendons

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32853181

Citation

Feng, Heng, et al. "Tendon-derived Cathepsin K-expressing Progenitor Cells Activate Hedgehog Signaling to Drive Heterotopic Ossification." The Journal of Clinical Investigation, vol. 130, no. 12, 2020, pp. 6354-6365.
Feng H, Xing W, Han Y, et al. Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification. J Clin Invest. 2020;130(12):6354-6365.
Feng, H., Xing, W., Han, Y., Sun, J., Kong, M., Gao, B., Yang, Y., Yin, Z., Chen, X., Zhao, Y., Bi, Q., & Zou, W. (2020). Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification. The Journal of Clinical Investigation, 130(12), 6354-6365. https://doi.org/10.1172/JCI132518
Feng H, et al. Tendon-derived Cathepsin K-expressing Progenitor Cells Activate Hedgehog Signaling to Drive Heterotopic Ossification. J Clin Invest. 2020 12 1;130(12):6354-6365. PubMed PMID: 32853181.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification. AU - Feng,Heng, AU - Xing,Wenhui, AU - Han,Yujiao, AU - Sun,Jun, AU - Kong,Mingxiang, AU - Gao,Bo, AU - Yang,Yang, AU - Yin,Zi, AU - Chen,Xiao, AU - Zhao,Yun, AU - Bi,Qing, AU - Zou,Weiguo, PY - 2019/08/16/received PY - 2020/08/20/accepted PY - 2020/8/28/pubmed PY - 2021/2/17/medline PY - 2020/8/28/entrez KW - Bone disease KW - Mouse models KW - Stem cells KW - Therapeutics SP - 6354 EP - 6365 JF - The Journal of clinical investigation JO - J Clin Invest VL - 130 IS - 12 N2 - Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk+Scx+ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/32853181/Tendon_derived_cathepsin_K_expressing_progenitor_cells_activate_Hedgehog_signaling_to_drive_heterotopic_ossification_ L2 - https://doi.org/10.1172/JCI132518 DB - PRIME DP - Unbound Medicine ER -