2. Academic Validation
  3. Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification

Tendon-derived cathepsin K-expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification

  • J Clin Invest. 2020 Dec 1;130(12):6354-6365. doi: 10.1172/JCI132518.
Heng Feng 1,  Wenhui Xing 1,  Yujiao Han 1,  Jun Sun 1,  Mingxiang Kong 2,  Bo Gao 1 3,  Yang Yang 1,  Zi Yin 4,  Xiao Chen 4,  Yun Zhao 1,  Qing Bi 2,  Weiguo Zou 1 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou, China.
  • 3 Institute of Orthopedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 4 Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China.
  • 5 Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
PMID: 32853181 DOI: 10.1172/JCI132518
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.

Keywords

Bone disease; Mouse models; Stem cells; Therapeutics.

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