Emerging molecular mechanisms of the ECM-exosome growth-plate axis in idiopathic short stature

Idiopathic short stature (ISS) remains a clinically heterogeneous diagnosis in which impaired linear growth is often defined by exclusion rather than by mechanism. Increasing evidence suggests that ISS and related short-stature phenotypes may converge on overlapping growth-plate abnormalities characterised by disrupted chondrocyte proliferation, hypertrophic differentiation, extracellular matrix (ECM) maturation, mineralisation, and endochondral ossification. In this narrative review, we synthesize current evidence relevant to a proposed ECM-exosome growth-plate axis as a hypothesis-generating framework for ISS. The reviewed studies suggest that exosomal RNA dysregulation, ECM structural abnormalities, growth-hormone and insulin-like growth factor signalling variation, environmental and inflammatory exposures, and altered local signalling pathways may each contribute to impaired growth-plate output in specific experimental or clinical contexts. However, these diverse upstream routes appear to be associated with overlapping downstream abnormalities in chondrocyte state transition and cartilage-to-bone conversion. We propose that the cartilage ECM may function as a regulatory niche that could influence exosome diffusion, retention, uptake, spatial exposure, and RNA signalling activity within growth-plate chondrocytes. Conversely, exosomal miRNAs, lncRNAs, and circRNAs may regulate ECM synthesis, matrix remodelling, hypertrophy, and ossification. Accordingly, the axis is presented here as a hypothesis-generating model rather than as an established causal mechanism in ISS. Nevertheless, direct causal evidence remains limited, particularly regarding whether ECM composition, stiffness, proteoglycan density, collagen organisation, or mineralisation state governs exosome-mediated RNA delivery in human growth-plate models. Future studies should combine paediatric cohorts, human chondrocytes, growth-plate organoids, hPSC-derived cartilage systems, engineered exosomes, and ECM perturbation-rescue experiments to validate this axis. Defining ECM-exosome signatures may enable mechanism-based ISS subclassification, prediction of GH responsiveness, liquid-biopsy biomarker development, and growth-plate-targeted therapeutic strategies. Overall, the proposed ECM-exosome growth-plate axis may help frame ISS as a potentially molecularly stratifiable disorder involving chondrocyte state-transition failure, rather than solely as an endocrine diagnosis of exclusion.