Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology.
Parathyroid Hormone-related Protein (PTHrP) has been shown to be essential for the development and homeostatic regulation of lung and bone. Since both lung and bone structure and function are affected by microgravity, we hypothesized that 0 x g down-regulates PTHrP signaling. To test this hypothesis, we suspended lung and bone cells in the simulated microgravity environment of a Rotating Wall Vessel Bioreactor, which simulates microgravity, for up to 72 hours. During the first 8 hours of exposure to simulated 0 x g, PTHrP expression fell precipitously, decreasing by 80-90%; during the subsequent 64 hours, PTHrP expression remained at this newly established level of expression. PTHrP production decreased from 12 pg/ml/hour to 1 pg/ml/hour in culture medium from microgravity-exposed cells. The cells were then recultured at unit gravity for 24 hours, and PTHrP expression and production returned to normal levels. Based on these findings, we have obtained bones from rats flown in space for 2 weeks (Mission STS-58, SL-2). Analysis of PTHrP expression by femurs and tibias from these animals (n=5) revealed that PTHrP expression was 60% lower than in bones from control ground-based rats. Interestingly, there were no differences in PTHrP expression by parietal bone from space-exposed versus ground-based animals, indicating that the effect of weightlessness on PTHrP expression is due to the unweighting of weight-bearing bones. This finding is consistent with other studies of microgravity-induced osteoporosis. The loss of the PTHrP signaling mechanism may be corrected using chemical agents that up-regulate this pathway. In conclusion, PTHrP represents a stretch-sensitive paracrine signaling mechanism that may sense gravity.
Harbor-UCLA Research & Education Institute, Departments of Pediatrics and Obstetrics and Gynecology, Torrance, California, 90502-2066, USA. jtorday@gcrc.rei.edu
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Torday
D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D019149:Bioreactors; D001842:Bone and Bones / Q000166:cytology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000502:physiology; D005269:Femur / Q000166:cytology / Q000502:physiology; D006112:Gravitation; D018466:Gravity Sensing / Q000502:physiology*; D008168:Lung / Q000166:cytology; D012516:Osteosarcoma; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D010294:Parietal Bone / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012399:Rotation; D013026:Space Flight; D013977:Tibia / Q000166:cytology / Q000502:physiology; D014162:Transfection; D014893:Weightlessness; D018474:Weightlessness Simulation
D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger