Significance of Parathyroid Hormone-Related Protein in Osteoblast Response to Microgravity
In elderly, bone loss due to osteoporosis (OP) is the most common cause of fractures. Extended skeletal unloading through bedrest results in bone loss similar to that observed in osteoporotic elderly patients, but with an accelerated timeframe. Astronauts lose up to 2% of their bone mass per month during the time spent in space which can also be considered due to the rapid effect on weight-bearing bones. The exact mechanisms involved in disuse osteoporosis have not been resolved, despite the important implications for spaceflight travelers and bedridden patients.
Parathyroid hormone-related protein (PTHrP) has been recommended as a mechanosensor which modulates many physiological processes including skeletal development. Trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual spaceflight for 6 days (Foton M3 satellite) to evaluate the role of PTHrP in microgravity-induced bone loss. For varying the duration from 6 days to 6 weeks, Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity. As COs exhibited little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Also, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. After 6 days in simulated 0g, microarray analysis of Pthrp+/+ TOs depicted expression changes in genes encoding prolactins, bone metabolism and extra-cellular matrix composition proteins, insulin-like growth factor family members, apoptosis/survival molecules, chemokines and Wnt-related signaling molecules. In normal gravity, 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation. Pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced changes in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to obstruct microgravity-induced cell death in TOs.