Genetic control of bone structure

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PI: van der Meulen, Marjolein C.Proposal #: 1605935The bones of the skeleton consist of two tissue structures: cortical bone, a high volume fraction material forming the outer shell and central shafts of long bones; and, cancellous bone, an open lattice with high porosity located in the interior and bone ends. To date bone tissue engineering has not considered the distinct genetic regulation of these two structures. The goal of this work is to examine age-related genetic and molecular mechanisms in the context of regulation of cancellous and cortical bone separately. Information obtained is critical to understanding and replicating bone tissue formation, maintenance and degeneration. The novel data will be used to identify genetic targets and pathways to inhibit or stimulate gene expression and/or envelope-specific signaling mechanisms to stimulate and enhance bone formation in vivo. The major broader impact objectives are focused on using this research and the PI's administrative role to enhance the participation of women in STEM education and academic careers. This award is co-funded by the Biomaterials program in the Division of Materials Research through the BioMaPs program.The bones of the skeleton consist of two tissue structures: cortical bone, a high volume fraction material forming the outer shell and central shafts of long bones; and, cancellous bone, an open lattice with high porosity located in the interior and bone ends. Thus their distinct genetic control is critical if one seeks to replicate these two structures. Cancellous and cortical bone have different developmental pathways and adapt differently to biophysical stimuli. For example, mechanical loading is an anabolic biophysical srtimulus that increases bone mass and can reverse bone loss in the adult. Mechanobiologic adaptation differs and is specific to cancellous or cortical bone. The two structures are differentially affected by disease, often with greater cancellous effect than cortical. The differing responses likely reflect different developmental and mechanosensory gene regulation between the two tissues. However, gene expression in the individual tissue structures has not been examined during growth or with adaptation to loading. The pathways underlying skeletal gene expression have been studied using knockout mice or with gene analyses of whole bones that do not differentiate between the two tissue types. The overall hypothesis of the proposed work is that gene expression differs in cortical and cancellous bone in vivo, leading to differential gene expression between the two tissues during growth and with perturbations such as mechanical loading. The research team has demonstrated: cancellous and cortical bone can be isolated individually from the tibial metaphysis of growing mice; sufficient mRNA is available and suitable for transciptomics; and, cancellous and cortical bone express different genes in growing mice. Using RNA-sequencing and pathway analysis, this project will 1) quantitate age-related gene expression in cancellous and cortical bone separately in the tibiae of growing and adult female mice; and, 2) identify potential new targets to stimulate anabolic bone formation using differential gene expression in the tibia of growing and adult female mice after in vivo loading, a mechanotransduction model developed by the PI's laboratory that differentially affects cancellous and cortical bone tissue. Information obtained is critical to understanding and replicating bone tissue formation, maintenance and degeneration. The novel data will be used to identify genetic targets and pathways to inhibit or stimulate gene expression and/or envelope-specific signaling mechanisms to stimulate and enhance bone formation in vivo. The major broader impact objectives are focused on using this research and the PI's administrative role to enhance the participation of women in STEM education and academic careers. Specifically the PI will: 1) engage middle school girls in STEM learning via workshops based on the proposed research; 2) involve female students in her research laboratory; and, 3) increase women faculty in STEM departments in academia.