Enhanced BMP signaling in Cathepsin K-positive tendon progenitors induces heterotopic ossification

Hiroyuki Yamaguchi; Margaret Li; Megumi Kitami; Sowmya Swaminathan; Yuji Mishina; Yoshihiro Komatsu

doi:10.1016/j.bbrc.2023.149147

Enhanced BMP signaling in Cathepsin K-positive tendon progenitors induces heterotopic ossification

Biochem Biophys Res Commun. 2023 Dec 25:688:149147. doi: 10.1016/j.bbrc.2023.149147. Epub 2023 Oct 24.

Authors

Hiroyuki Yamaguchi¹, Margaret Li², Megumi Kitami³, Sowmya Swaminathan⁴, Yuji Mishina⁵, Yoshihiro Komatsu⁶

Affiliations

¹ Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
² Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA; Department of Kinesiology, Rice University Wiess School of Natural Science, Houston, TX, 77005, USA.
³ Division of Dental Pharmacology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8514, Japan; Center for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8514, Japan.
⁴ Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA; The College of Natural Sciences, The University of Texas at Austin, Austin, TX, 78712, USA.
⁵ Department of Biologic and Materials Sciences & Prosthodontics, School of Dentistry, University of Michigan, Ann Arbor, MI, 48109, USA.
⁶ Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA; Graduate Program in Genetics and Epigenetics, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, 77030, USA. Electronic address: Yoshihiro.Komatsu@uth.tmc.edu.

PMID: 37948912
PMCID: PMC10952113 (available on 2024-12-25)
DOI: 10.1016/j.bbrc.2023.149147

Abstract

Heterotopic ossification (HO) is abnormal bone growth in soft tissues that results from injury, trauma, and rare genetic disorders. Bone morphogenetic proteins (BMPs) are critical osteogenic regulators which are involved in HO. However, it remains unclear how BMP signaling interacts with other extracellular stimuli to form HO. To address this question, using the Cre-loxP recombination system in mice, we conditionally expressed the constitutively activated BMP type I receptor ALK2 with a Q207D mutation (Ca-ALK2) in Cathepsin K-Cre labeled tendon progenitors (hereafter "Ca-Alk2:Ctsk-Cre"). Ca-Alk2:Ctsk-Cre mice were viable but they formed spontaneous HO in the Achilles tendon. Histological and molecular marker analysis revealed that HO is formed via endochondral ossification. Ectopic chondrogenesis coincided with enhanced GLI1 production, suggesting that elevated Hedgehog (Hh) signaling is involved in the pathogenesis of HO. Interestingly, focal adhesion kinase, a critical mediator for the mechanotransduction pathway, was also activated in Ca-Alk2:Ctsk-Cre mice. Our findings suggest that enhanced BMP signaling may elevate Hh and mechanotransduction pathways, thereby causing HO in the regions of the Achilles tendon.

Keywords: BMP signaling; Hedgehog signaling; Heterotopic ossification; Mechanotransduction; Mouse.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cathepsin K / metabolism
Hedgehog Proteins
Mechanotransduction, Cellular*
Mice
Ossification, Heterotopic* / metabolism
Tendons / metabolism

Substances

Cathepsin K
Hedgehog Proteins

Grants and funding

R01 DE025897/DE/NIDCR NIH HHS/United States