SERRAT, M.A.*; LOVEJOY, C.O.; KING, D.; Kent State University, OH; Kent State University, OH; NEOUCOM, Rootstown, OH: Age- and site-specific decline in IGF-I receptor expression and growth plate activity in the mouse hindlimb

The proximal and distal growth plates of the principal long bones do not contribute equally to their longitudinal growth. Most hindlimb elongation occurs at the knee (distal femur/proximal tibia), while the forelimb grows predominantly at the shoulder (proximal humerus) and wrist (distal radius/ulna). Much diversity in mammalian limb proportions is realized through these differences in local physis growth, but the mechanisms that underlie them remain unclear. We tested the hypothesis that expression of the insulin-like growth factor-I receptor (IGF-IR) is associated with differential growth in the mouse hindlimb. We evaluated IGF-IR expression in proximal/distal growth plates of the femur and tibia from 8, 16, and 28 day old mice using immunohistochemistry. Growth activity was assessed by size/morphology of the growth plate and PCNA staining for proliferation. IGF-IR and PCNA positive cells were counted and standardized as a proportion of the total chondrocytes in each growth plate. Cells expressing the IGF-IR declined considerably with age in the proximal femur and distal tibia (hip and ankle), but maximum expression was maintained in the distal femur and proximal tibia (knee) at all ages. PCNA expression similarly declined with age in the hip and ankle but remained high in the knee. 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.