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

The growth plate is regulated by complex local mechanisms, and therapies like vosoritide may offer new avenues for treating specific growth disorders, though most children with short stature remain outside this paradigm.

Summary and findings

This mini-review discusses the role of chondrocyte biology and the growth hormone-insulin-like growth factor 1 axis in childhood growth. It highlights the mechanisms of growth plate senescence and the potential for targeted therapies like vosoritide. The review emphasizes the complexity of growth regulation beyond systemic hormones.

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 <i>SHOX</i> 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.

Limitations

Not reported in abstract.

Elsewhere in the Vosoritide corpus