Abstract
Bone cells sense and actively adapt to physical perturbations to prevent critical damage. ATP release is among the earliest cellular responses to mechanical stimulation. Mechanical stimulation of a single murine osteoblast led to the release of 70 ± 24 amole ATP, which stimulated calcium responses in neighboring cells. Osteoblasts contained ATP-rich vesicles that were released upon mechanical stimulation. Surprisingly, interventions that promoted vesicular release reduced ATP release, while inhibitors of vesicular release potentiated ATP release. Searching for an alternative ATP release route, we found that mechanical stresses induced reversible cell membrane injury in vitro and in vivo. Ca2+/PLC/PKC-dependent vesicular exocytosis facilitated membrane repair, thereby minimizing cell injury and reducing ATP release. Priming cellular repair machinery prior to mechanical stimulation reduced subsequent membrane injury and ATP release, linking cellular mechanosensitivity to prior mechanical exposure. Thus, our findings position ATP release as an integrated readout of membrane injury and repair.
Highlights
The mechanical environment is an important determinant of bone health, as emphasized by a consistent bone loss in astronauts exposed to microgravity or in paralyzed or bedridden patients (Nagaraja and Jo, 2014)
Since we have previously demonstrated that transient membrane disruption is required to induce global [Ca2+]i elevations in osteoblasts (Lopez-Ayon et al, 2014), we were interested in understanding the contribution of membrane injury to mechanically induced ATP release
We established the regulatory mechanisms involved in controlling the amount of ATP released following reversible cellular injury
Summary
The mechanical environment is an important determinant of bone health, as emphasized by a consistent bone loss in astronauts exposed to microgravity or in paralyzed or bedridden patients (Nagaraja and Jo, 2014). Bone-embedded osteocytes and bone-forming osteoblasts are widely regarded as the mechanosensitive cells in the skeletal system (Weinbaum et al, 1994). Following mechanical stimulation of rodent and human osteoblasts, transient intracellular free calcium ([Ca2+]i) elevations and ATP release are among the earliest detectable events, which result in autocrine and paracrine purinergic (P2) receptor signaling (Robling and Turner, 2009; Romanello et al, 2001; Genetos et al, 2005). Non-lethal membrane injury has been demonstrated in vivo in several tissues (McNeil and Steinhardt, 2003), including bone (Yu et al, 2017), under physiological conditions. The mechanism of facilitated cell membrane repair has been described and involves Ca2+/PKC-dependent vesicular exocytosis (Togo et al, 1999). The contribution of non-lethal cell injury to ATP release and related mechanotransductive purinergic signaling remains unclear
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