Growth plate closure and therapeutic interventions.

Height gains result from longitudinal bone growth, which is largely dependent on chondrocyte differentiation and proliferation within the growth plates of long bones. The growth plate, that is, the epiphyseal plate, is divided into resting, proliferative, and hypertrophic zones according to chondrocyte characteristics. The differentiation poten-tial of progenitor cells in the resting zone, continuous capacity for chondrocyte differentiation and proliferation within the proliferative zone, timely replacement by osteocytes, and calcification in the hypertrophic zone are the 3 main factors controlling longitudinal bone growth. Upon ade quate longitudinal bone growth, growth plate senescence limits human body height. During growth plate senescence, progenitor cells within the resting zone are deplet ed, proliferative chondrocyte numbers de crease, and hypertrophic chondrocyte number and size decrease. After senescence, hypertrophic chondrocytes are replaced by osteocytes, the extracellular matrix is calcified and va-scularized, the growth plate is closed, and longitudinal bone growth is complete. To date, go nadotropin-releasing hormone analogs, aromatase inhi bitors, C-type natriuretic peptide analogs, and fibroblast growth factor receptor 3 inhibitors have been studied or used as therapeutic interv-entions to delay growth plate closure. Complex networks of cellular, genetic, paracrine, and endocrine signals are involved in growth plate closure. However, the detailed mechanisms of this process remain unclear. Further eluci-dation of these mechanisms will enable the development of new thera peutic modalities for the treatment of short stature, precocious puberty, and skeletal dysplasia.