4.6 Article

Single cell analysis reveals inhibition of angiogenesis attenuates the progression of heterotopic ossification in Mkx-/- mice

Journal

BONE RESEARCH
Volume 10, Issue 1, Pages -

Publisher

SPRINGERNATURE
DOI: 10.1038/s41413-021-00175-9

Keywords

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Funding

  1. National Key R&D Program of China [2017YFA0104900]
  2. National Natural Science Foundation of China [31830029, 81501937, 81522029]
  3. Fundamental Research Funds for the Central Universities [K20200099]

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This study investigates the pathological mechanism of tendon heterotopic ossification (HO) and proposes a potential treatment method. The expression level of Mohawk (MKX) is decreased in HO tissue, which is correlated with the upregulation of osteochondrogenic and angiogenic gene expression. Single-cell RNA sequencing analysis reveals the excessive activation of osteochondrogenic genes in Mkx(-/-) tendon cells during tenogenesis. Inhibition of angiogenesis using the small-molecule inhibitor BIBF1120 attenuates bone formation and angiogenesis in both Mkx mutant mice and a rat traumatic model of HO.
Tendon heterotopic ossification (HO) is characterized by bone formation inside tendon tissue, which severely debilitates people in their daily life. Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis. Here, we investigate the pathological mechanism and propose a potential treatment method for HO. Immunofluorescence assays showed that the Mohawk (MKX) expression level was decreased in human tendon HO tissue, coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx(-/-) mice. Single-cell RNA sequencing analyses of wild-type and Mkx(-/-) tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx(-/-) tendon cells. Single-cell analysis revealed that the gene expression program of angiogenesis, which is strongly associated with bone formation, was activated in all cell types during HO. Moreover, inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO. These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.

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