Testosterone stimulates insulin-like growth factor-I and insulin-like growth factor-I-receptor gene expression in the mandibular condyle - A model ofendochondral ossification

Puberty is associated with an increase in the plasma concentration of sex s teroids, GH, and insulin-like growth factor-I (IGF-I). Gonadal steroid horm ones are important for the normal pubertal growth spurt and skeletal growth . The mechanism by which gonadal steroids induce skeletal growth is still n ot fully understood. To better understand the direct effect sex steroids ha ve on bone growth, we studied an isolated organ culture system of the mandi bular condyle, derived from 3.5-5.5-week-old male and female mice. We found that testosterone 10(-6) M, but not estradiol, stimulated thymidine incorp oration into the DNA of male-derived condyle. Three days of testosterone tr eatment doubled the condyle size and increased the chondroprogenitor zone, while maintaining the normal gradient of the developing chondrocytes. Immun ohistochemistry and in situ hybridization techniques showed that testostero ne stimulated IGF-I and IGF-I-R and their messenger RNAs (mRNAs) mainly in the mature chondrocyte layer. Immunoneutralization of IGF-I in the testoste rone-treated condyle caused the disappearance of the chondroblast and young chondrocyte layers, though the progenitor cell layer remained almost unaff ected. Overtreatment with testosterone (dose or duration) accelerated condy lar ossification. In the presence of testosterone 10(-5) M (high dose), cal cification "climbs" up to the chondroprogenitor zone, and most of the condy lar chondrocytes are replaced by bone tissue. Similar changes occurred afte r 7 days of testosterone treatment (long duration) with 10(-6) M. In conclu sion, testosterone stimulates growth and local production of IGF-I and IGF- I-R in chondrocyte cell layers of an isolated organ culture of mice mandibu lar condyle. Part of the effect testosterone has on condylar growth is medi ated by IGF-I.