Disrupted Growth Plate Hypertrophy in X-Linked Hypophosphatemia: Insights from 3D Morphological Analysis

Abstract

X-linked Hypophosphatemia (XLH) is a rare disorder ranking among the most common inherited forms of rickets. XLH arises from 
mutations in the PHEX gene which leads to increased levels of the phosphaturic hormone FGF23, disrupting vitamin D metabolism 
and causing an imbalance in phosphate homeostasis. This cascade of events manifests in characteristic features including short 
stature, leg bowing, dental anomalies, and bone deformities. While growth impairment is a prominent feature, limited research 
focuses on the mechanism underlying this growth arrest.
 The Growth Plate (GP) cells undergo differentiation and hypertrophy, ultimately transforming into bone-forming cells or providing 
space for new bone formation. Although final length is directly related with final chondrocyte size, in XLH and other growth 
disorders, little is known about the hypertrophy process, likely due to the GP heterogeneity and complexity. This study utilized 
advanced three-dimensional morphological analyses of the growth plate of young XLH mice, providing a comprehensive view 
growth plate mineralization. The integrated approach revealed that growth plate can be divided in more than the 3 classical zones 
and determines molecular signatures mainly affecting hypertrophy zone in XLH. Indicating that these cells are not able to final 
differentiate and hypertrophy and therefore synthesize matrix proteins properly, forming eventually an aberrant extrapolation of 
cells identified as cluster 8 in confocal microscopy. Therefore, these findings highlight an alteration of ECM, in turn, changes 
the biomechanical environment of articulations independently of grade of bone bowing. This further will drive the progression 
of degenerative disease as Osteoarthritis even in presence of bone surgery correction. This study enhances our comprehension of 
XLH’s impact on skeletal development and illuminate the underlying molecular mechanisms governing longitudinal bone growth.