Porcupine inhibition enhances hypertrophic cartilage differentiation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F25%3A00635884" target="_blank" >RIV/67985904:_____/25:00635884 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14310/25:00144328

Result on the web

<a href="https://academic.oup.com/jbmrplus/article/9/6/ziaf048/8099953?login=true" target="_blank" >https://academic.oup.com/jbmrplus/article/9/6/ziaf048/8099953?login=true</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/jbmrpl/ziaf048" target="_blank" >10.1093/jbmrpl/ziaf048</a>

Result language

angličtina

Original language name

Porcupine inhibition enhances hypertrophic cartilage differentiation

Original language description

Porcupine (PORCN) is a membrane-bound protein of the endoplasmic reticulum, which modifies Wnt proteins by adding palmitoleic acid. This modification is essential for Wnt ligand secretion. Patients with mutated PORCN display various skeletal abnormalities likely stemming from disrupted Wnt signaling pathways during the chondrocyte differentiation. To uncover the mechanism of PORCN action during chondrogenesis, we used 2 different PORCN inhibitors, C59 and LGK974, in several model systems, including micromasses, 3D cell cultures, long bone tissue cultures, and zebrafish animal model. PORCN inhibitors enhanced cartilaginous extracellular matrix (ECM) production and accelerated chondrocyte differentiation, which resulted in the earlier induction of cellular hypertrophy as well as cartilaginous mass expansion in micromass cultures and cartilaginous organoids. In addition, both PORCN inhibitors expanded the hypertrophic zone and reduced the proliferative zone in the growth plate. This led to a significant increase in cartilaginous tissue and ultimately resulted in the elongation of tibias in the mouse organ cultures. Also, LGK974 treatment of Danio rerio embryos induced expansion of craniofacial cartilage width together with the shortening of the body axis, which was consistent with a phenomenon occurring upon inhibition of non-canonical Wnt signaling. By combining PORCN inhibition with exogenous Wnt proteins activating either canonical/beta-catenin (WNT3a) or non-canonical (WNT5a) signaling, we propose that the key mechanism mediating pro-chondrogenic effects of PORCN inhibition is the removal of canonical ligands that prevent chondrocyte differentiation. In summary, our results provide evidence of the distinct role of PORCN in both the early and late stages of cartilage development. Further, our data demonstrate that PORCN inhibitors can be used in the experimental and clinical strategies that need to trigger chondrocyte differentiation and/or cartilage outgrowth.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10605 - Developmental biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

JBMR Plus

ISSN

2473-4039

e-ISSN

2473-4039

Volume of the periodical

9

Issue of the periodical within the volume

6

Country of publishing house

GB - UNITED KINGDOM

Number of pages

24

Pages from-to

ziaf048

UT code for WoS article

001492658400001

EID of the result in the Scopus database

2-s2.0-105006499962