Age- and site-specific decline in insulin-like growth factor-I receptor expression is correlated with differential growth plate activity in the mouse hindlimb

The proximal and distal growth plates of the principal long bones do not contribute equally to longitudinal growth. Most forelimb elongation occurs at the shoulder and wrist, while most hindlimb growth occurs at the knee. This study examined whether insulin-like growth factor-I (IGF-I), a potent growth regulator, could underlie this variation via differential receptor expression. The spatiotemporal distribution of the IGF-I receptor (IGF-IR) was mapped in hindlimb growth plates (overall and within regional zones) from immature mice using immunohistochemistry. Growth activity was assessed by size/morphology of the growth plate and proliferating cell nuclear antigen (PCNA) expression. Both IGF-IR and PCNA staining declined considerably with age in the proximal femur and distal tibia (hip and ankle), but expression remained high in the more active distal femur and proximal tibia (knee) throughout growth. Growth plate size decreased with age in all sites, but the absolute and relative decline in IGF-IR in the hips and ankles of older mice indicated a site-specific loss of IGF-I sensitivity in these less active regions. These results suggest that regulation of the IGF-IR may at least partially mediate differential long bone growth, thereby providing a local mechanism for altering skeletal proportions absent modification of systemic hormone levels.