ESPE Yearbook of Paediatric Endocrinology

J Bone Miner Res 36, 1387–1402. (2021)Abstract: https://pubmed-ncbi-nlm-nih-gov/33724538/

In brief: Premature growth plate closure under anti-hedgehog treatment is caused by impaired retinoic acid metabolism in growth plate progenitor cells. In this mouse model, administration of retinoic acid receptor blockers rescued the phenotype and normalized growth plate maturation.

Commentary: With the increasing use of pathway inhibitor therapies in paediatric oncology, unintended effects such as affection of growth plate cartilage have become an imminent clinical challenge. In the present study, Koyama et al investigated the mechanism and pharmacologic interventions regarding premature growth plate closure associated with the hedgehog inhibitor Sondegib. In a murine model system, Sondegib decreased growth plate progenitor cell number and proliferation rate. On an expressional level, retinoid metabolism was altered towards higher local levels of retinoic acid, inducing a profound acceleration of growth plate maturation. In vivo treatment with a selective retinoic acid inhibitor could entirely rescue the phenotype by normalizing long bone growth. In vitro, micromass cultures of embryonic mesenchymal cell marker gene expression such as Col2a1, Col10a1 and Sox9 as shown by in situ hybridisation revealed normalized patterns after coadministration of the Sondegib and a retinoic acid inhibitor.

Koyama et al systematically approached the phenomenon of growth plate progenitor cell depletion under Sondegib treatment. By analysing the treatment effects, hedgehog signalling was identified as crucial regulator of this important cell population mainly by keeping a local state devoid from retinoic acid action. Since the effects of retinoic acid receptor antagonist co-treatments on the oncologic efficacy of hedgehog inhibition has not been tested, the direct clinical relevance of the findings has to be proven in future studies. Nevertheless, these data add a fascinating chapter to the complex regulation of growth plate progenitor cells which may aid future therapeutic aspects targeting the growth plate.