THE MOLECULAR RESPONSE OF BONE TO GROWTH-HORMONE DURING SKELETAL UNLOADING - REGIONAL DIFFERENCES

Hind limb elevation of the growing rat provides a good model for the s keletal changes that occur during space flight. In this model the bone s of the forelimbs (normally loaded) are used as an internal control f or the changes that occur in the unloaded bones of the hind limbs. Pre vious studies have shown that skeletal unloading of the hind limbs res ults in a transient reduction of bone formation in the tibia and femur , with no change in the humerus. This fall in bone formation is accomp anied by a fall in serum osteocalcin (bone Gla protein, BGP) and bone BGP messenger RNA (mRNA) levels, but a rise in bone insulin-like growt h factor-I (IGF-I) protein and mRNA levels and resistance to the skele tal growth-promoting actions of IGF-I. To determine whether skeletal u nloading also induced resistance to GH, we evaluated the response of t he femur and humerus of sham and hypophysectomized rats, control and h ind limb elevated, to GH (two doses), measuring mRNA levels of IGF-I, BGP, rat bone alkaline phosphatase (RAP), and alpha(1)(1)-procollagen (cell). Hypophysectomy (HPX) decreased the mRNA levels ofIGF-I, BGP, a nd cell in the femur, but was either less effective or had the opposit e effect in the humerus. GH at the higher dose (500 mu g/day) restored these mRNA levels to or above the sham control values in the femur, b ut generally had little or no effect on the humerus. RAP mRNA levels w ere increased by HPX, especially in the femur. The lower dose of GH (5 0 mu g/day) inhibited this rise in RAP, whereas the higher dose raised the mRNA levels and resulted in the appearance of additional transcri pts not seen in controls. As for the other mRNAs, RAP mRNA in the hume rus was less affected by HPX or GH than that in the femur. Hind limb e levation led to an increase in IGF-I, cell, and RAP mRNAs and a reduct ion in BGP mRNA in the femur and either had no effect or potentiated t he response of these mRNAs to GH. We conclude that GH stimulates a num ber of markers of bone formation by raising their mRNA levels, and tha t skeletal unloading does not block this response, but the response va ries substantially from bone to bone.