NSF Award
1727949
Exercise (bone mechanical loading) is crucial for maintenance of bone health. Bone adjusts to its loading environment; the skeleton strengthens from mechanical loading and weakens when not used. During aging, the ability of bone to properly sense and respond to mechanical loading can change, contributing to the development of osteoporosis and placing individuals at risk of skeletal fractures. Cells embedded within bone matrix called osteocytes sense mechanical load and use it as a signal to direct skeletal adaptation. The mechanisms osteocytes use to detect loading are not fully understood, but if discovered, could be targeted by medical treatments intended to prevent osteoporotic fractures. The research will advance this field by examining a novel mechanism to detect bone loading, where osteocytes develop small tears in their cell membrane during mechanical loading. A cell membrane tear triggers cell responses in the wounded and in neighboring non-wounded cells that are known to be associated with mechanical loading. The objective of this research program is to determine the role of loading-induced plasma membrane tears in osteocyte mechanosensation. Once this biology is better understood, it can be investigated as a contributing factor to regulation of bone mass (e.g., during aging) and targeted to test therapeutic agents for altering membrane fragility and repair rates in bone to enhance skeletal responses to loading. The PI particpates in a pipeline established to recruit graduate students, undergraduate students, and fellows from schools serving under-represented hispanic minorities in Puerto Rico. Outreach to K-12 students, in the form of STEM seminars, Career Day presentations, and Science Fair judging, will be performed by the PI and students. Research findings will be integrated into lectures to give students a deeper appreciation for the material than they would gain from a purely "textbook" lecture and to attract students into research activities.<br/><br/>Evolution restricts musculoskeletal tissue growth to minimize the metabolic and biomechanical expense of excess tissue mass, which explains why mechanically regulated inhibitors of musculoskeletal growth (e.g., sclerostin and myostatin) exist. Likewise, it would be evolutionarily beneficial for the initiating stimulus for adaptation (mechanosensation mechanism) to specifically recognize injurious mechanical stressors, so that tissue adaptation would be driven by a mechanobiological need to preserve cell viability and organ integrity. This project poses that mechanical loading causes repairable plasma membrane injury in osteocytes, which triggers a signal cascade leading to bone adaptation. Thus, mechanically loaded bone adapts in part by sensing cellular injury, and adaptation in the form of altered geometry and tissue properties may be designed to limit future injury when similar stresses are imposed. This project will advance the fundamental understanding of osteocyte mechanosensation, addressing an unanswered question in the field and providing new avenues to augment bone strength. Goals include defining how membrane tears arise and initiate signaling in osteocytes, testing the effects of altering membrane repair, and exploring how these mechanisms affect osteocyte mechanosensation during aging. Experiments will employ state-of-the-art imaging and multiscale studies of bone mechanosensitivity.
