Skeletal Response to Applied Mechanical Loads in the Mouse Tibia

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The bones of the skeleton contain two tissue structures: (1) dense cortical bone, a high volume fraction material forming the outer shell and central shafts of long bones, and, (2) low volume fraction cancellous bone, an open-­lattice structure located in the interior and ends of bones. In general, these two structures are treated simply as a single material, 'bone' rather than distinguishing their individual characteristics. However, cancellous and cortical bone have different developmental pathways and adapt differently to biophysical stimuli, particularly mechanical loading. Loads applied to the skeleton are anabolic, increasing bone mass and reversing bone loss in the adult. The overall hypothesis of this work is that in vivo loading drives quantitative gene expression differently in cortical and cancellous bone, leading to differential responses to mechanical loading with age and location. This research has potential to benefit society through the identification of genetic targets to stimulate bone formation, which is critical to aging and musculoskeletal conditions such as osteoporosis and joint replacement. Gene expression has not been analyzed in a tissue-­envelope-­specific manner in bone despite these approaches having revolutionized other fields. As an integral part of this research, the principal investigator plans several efforts to increase the participation of women in science. Specifically she will, (1) engage middle school girls in STEM learning via workshops based on this research; (2) involve female students in her research laboratory; and, (3) work to increase representation of women faculty in STEM departments in academia at Cornell and nationwide.Using state-­of-­the-­art next generation gene sequencing techniques, this work will identify skeletal molecular mechanisms that are activated in response to mechanical stimuli. In the first objective, the emphasis will be on the regulation of mechanobiologic bone formation in cancellous and cortical tissue separately. Using controlled in vivo loading of the tibia in growing and adult female mice, changes in gene expression and protein localization will be determined using methods to isolate the tissues in the mouse proximal tibia. Thereafter, the specific relationship between the magnitude of loading and the tissue response will be studied in cortical bone. Here the goal will be to identify signaling pathways within the cortex associated with axially-­varying load magnitude along the diaphysis of the tibia in growing female mice. This work will identify future targets to inhibit or stimulate gene expression and/or envelope-­specific signaling mechanisms to enhance bone formation in vivo. Ultimately these results may allow stimulation of bone mass in vivo in a tissue-­specific fashion to decrease suffering and economic burden in individuals with musculoskeletal disorders.