Growth plate senescence, chondrocyte biology, and the growth hormone–insulin-like growth factor 1 axis in childhood growth

Abstract

Abstract Longitudinal bone growth in children depends on endochondral ossification within the epiphyseal growth plate, a process long viewed as a passive readout of systemic hormones but now recognized as an actively regulated, self-limiting process. This mini-review synthesizes recent evidence on chondrocyte biology, growth plate senescence, and the growth hormone (GH)–insulin-like growth factor 1 (IGF-1) axis. Local paracrine networks establish precise antagonistic and synergistic interactions: fibroblast growth factor receptor 3 (FGFR3) suppresses chondrocyte proliferation via MAPK/STAT signaling, while the C-type natriuretic peptide/NPR2 pathway counters this via cGMP-mediated stimulation; the Indian hedgehog–parathyroid hormone–related protein feedback loop, the SHOX gene, and mechanical loading provide additional structural control. Growth plate senescence follows a proposed localized, cell-counting mechanism reflecting cumulative chondrocyte division that current evidence supports but that has not been established as the sole explanation for chronological variation in physeal closure. Estrogen is a key accelerant of this senescent process during puberty. Pathogenic variants in these local regulators underlie conditions such as achondroplasia and a minority of cases classified as idiopathic short stature, and mechanism-targeted therapies – including vosoritide, a C-type natriuretic peptide analog, together with the FGFR3-directed tyrosine kinase inhibitor infigratinib and the once-weekly CNP prodrug navepegritide – illustrate, for achondroplasia specifically, how targeting a defined paracrine lesion can produce growth responses that systemic hormone stimulation alone does not achieve in that disorder. For a limited group of monogenic growth-plate disorders, resolving these molecular networks is beginning to complement uniform systemic intervention with precision, mechanism-based therapy, although this paradigm remains investigational for the great majority of children with short stature.