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IMPACT OF SKELETAL UNLOADING ON BONE FORMATION.  D.D. Bikle, T. Sakata, H. Elalieh, B.P. Halloran.  University of California and Veterans Affairs Medical Center, San Francisco, CA 94121.

   Skeletal unloading whether it occurs in space or in bed results in a decrease in bone formation.  We have used the tail suspended rat model to study the mechanisms involved because this model simulates a number of physiologic effects of space travel including the cephalad fluid shift.  This model also provides a built in control in that the forelimbs remain normally weighted.  The tail suspended rat demonstrates a reversible inhibition of bone formation associated with decreased proliferation of osteoprogenitor cells and increased apoptosis of osteoblasts and osteocytes in the hindlimbs but not in the forelimbs. These results indicate that local factors are likely to dominate the response to unloading.  We have focused on IGF-I as the local factor in that it is produced by bone and stimulates bone formation.  Skeletal unloading results in resistance to the anabolic/proliferative actions of IGF-I. Recent data from our laboratory indicate that this resistance is at the receptor level.  IGF-I receptors in osteoprogenitor cells are not activated by IGF-I. This leads to a failure of MAPK/ERK and PI3K/AKT activation explaining both the decreased proliferation and increased apoptosis of osteoblasts, osteocytes, and their precursors with skeletal unloading.  The result is decreased bone formation with its attendant loss of bone. 

(Supported by NASA NAG-2-1371)

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