AUTOCRINE DOWN-REGULATION OF COLLAGENASE-3 IN RAT BONE CELL-CULTURES BY INSULIN-LIKE GROWTH-FACTORS

Insulin-like growth factors (IGF)-I and -II are presumed to act as aut ocrine regulators of bone formation. Recently, we demonstrated that IG F-I and -II inhibit bone collagen degradation and collagenase-3 synthe sis in osteoblast cultures. Therefore, we tested the autocrine role of IGFs in the endogenous expression of collagenase-3 in cultures of ost eoblast-enriched cells from 22-day fetal rat calvariae (Ob cells). Ste ady-state messenger RNA (mRNA) levels were determined by Northern blot analysis and collagenase concentrations in the culture medium were de termined by Western immunoblot. Basal level collagenase-3 transcripts decreased in Ob cell cultures, coinciding with an increase in IGF-I an d -II protein levels. Removal of the conditioned medium modestly incre ased collagenase-3 mRNA levels and restored the ability of exogenously added IGF-I to repress collagenase-3 transcripts. IGF neutralizing an tibodies and IGF binding proteins-2 and -3 in excess increased and sus tained collagenase mRNA, heterogeneous nuclear RNA, and protease level s in Ob cell cultures. In conclusion, IGF-I and -II are autocrine repr essors of collagenase-3 synthesis, and this effect may contribute to t heir actions on the maintenance of a normal bone collagen matrix.