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J Bone Miner Res. 2018 Nov 20. doi: 10.1002/jbmr.3630. [Epub ahead of print]

Mkx-deficient Mice Exhibit Hedgehog Signaling Dependent Ectopic Ossification in the Achilles Tendons.

Liu H1, Xu J1, Jiang R1,2,3,4.

Author information

1
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
2
Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
3
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
4
Shriners Hospitals for Children - Cincinnati, Cincinnati, Ohio, USA.

Abstract

Heterotopic ossification is the abnormal formation of mineralized bone in skin, muscle, tendon, or other soft tissues. Tendon ossification often occurs from acute tendon injury or chronic tendon degeneration, of which current treatment relies heavily on surgical removal of the ectopic bony tissues. Unfortunately, surgery creates additional trauma, which often causes recurrence of heterotopic ossification. The molecular mechanisms of heterotopic ossification are not well understood. Previous studies demonstrate that Mkx is a transcription factor crucial for postnatal tendon fibril growth. Here we report that Mkx-/- mutant mice exhibit ectopic ossification in the Achilles tendon within one month after birth and the tendon ossification deteriorates with age. Genetic lineage labeling revealed that the tendon ossification in Mkx-/- mice resulted from aberrant differentiation of tendon progenitor cells. Furthermore, tissue-specific inactivation of Mkx in tendon cells postnatally resulted in similar ossification phenotype, indicating that Mkx plays a key role in tendon tissue homeostasis. Moreover, we show that Hedgehog signaling is ectopically activated at early stages of tendon ossification and that tissue-specific inactivation of Smoothened, which encodes the obligatory transducer of Hedgehog signaling, in the tendon cell lineage prevented or dramatically reduced tendon ossification in Mkx-/- mice. Together, these studies establish a new genetic mouse model of tendon ossification and provide new insight into its pathogenic mechanisms. This article is protected by copyright. All rights reserved.

KEYWORDS:

BONE; GENETIC ANIMAL MODEL; HEDGEHOG; MKX; MOUSE; OSSIFICATION; SCX; SIGNALING; TENDON

PMID:
30458056
DOI:
10.1002/jbmr.3630

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