Abstract
Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs.
Highlights
Bone loss due to osteoporosis (OP) is the most common cause of fractures among the elderly
In order to investigate the role of Parathyroid hormone-related protein (PTHrP) in bone cells exposed to space microgravity, trabecular and calvarial osteoblasts obtained from bones of Pthrp -/- fetal mice and Pthrp +/+ littermates [26] were attached to CC2 culture slides and inserted into sterile bioreactors connected online to the automated experimental trays (Fig 1A)
For Pthrp -/- TOs, a 20.4 ± 5.0% increase in apoptotic cells was observed at 0g over the 6-day period compared to the equivalent Pthrp -/cells which had remained on Earth (Fig 1B white bars)
Summary
Bone loss due to osteoporosis (OP) is the most common cause of fractures among the elderly. Even a shortduration exposure to microgravity results in profound metabolic changes, and the lack of mechanical loading causes rapid demineralization in bones of the lower body leading to development of a disuse osteoporotic-like phenotype [4]. Microgravity-induced bone loss shows no sign of stabilization while at 0g and displays a highly-variable speed of skeletal recovery upon return to Earth [6,7,8,9,10]. The causes of this rapidly-progressing syndrome have not been elucidated, and only partially-effective countermeasures have been developed [11]
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