It is now known that small changes in bone adaption to mechanical load can lead to large changes in skeletal resistance to fracture. Osteocytes are believed to be the mechanosensory cells of bone receiving these physiological signals and responding in a manner to regulate their local microenvironment and to globally control bone formation and bone resorption in selective regions of bone. Dentin Matrix Protein 1, DMP1, and Matrix Extracellular Phosphoglycoprotein, MEPE, are highly expressed in osteocytes and respond to mechanical load. Both proteins are highly localized in the canaliculi and lacunae of osteocytes, with DMP1 found predominately on the canalicular walls. Our goal is to use these two genes as representative of osteocyte selective genes responsive to mechanical strain to identify molecular signalling mechanisms responsible for changes in bone properties. Our hypothesis is that specific osteocyte selective and mechanically responsive enhancer regions exist in the promoters of DMP1 and MEPE that are controlled by specific transcription family pathways in response to strain. To test this hypothesis three specific aims are proposed:
Specific Aim 1. Determine the relationship between DMP1 and MEPE gene expression patterns with strain field analysis upon mechanical loading in vivo.
Specific Aim 2. Determine the relationship of osteocyte deformation in the mouse ulna and femur to different levels of strain and gene activation of the DMP1 and MEPE cis-regulatory regions.
Specific Aim 3. Determine the cis-regulatory regions of the DMP1 and MEPE genes that control the response to loading selectively in osteocytes. This project is unique in that DMP1 and MEPE gene expression will be correlated with macroscopic strain in vivo and with local cell deformation ex vivo. These genes and their appropriate cis-regulatory regions linked to reporters will serve as sensitive read-outs of osteocyte responsiveness in different loading conditions in different genetic backgrounds. This project will be devoted to understanding the cis-regulatory systems of both the DMP1 and MEPE genes in terms of their osteocyte selectivity and to identifying transcription factors responsible for this selectivity and responsiveness to mechanical loading. The goals of this project will be accomplished using cell models to identify molecular mechanisms, animal models for in vivo validation, together with engineering principles, combined with a molecular and a systems biology approach. Increased fatigue resistance is a major means to prevent fracture. Mapping osteocyte genes and pathways that are selectively responsive to load will provide information important to prevention or treatment of bone disease such as disuse osteoporosis, post menopausal osteoporosis and other pathological conditions of bone loss.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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University of Missouri Kansas City
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Kitase, Yukiko; Vallejo, Julian A; Gutheil, William et al. (2018) ?-aminoisobutyric Acid, l-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor. Cell Rep 22:1531-1544
Jähn, Katharina; Kelkar, Shilpa; Zhao, Hong et al. (2017) Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo. J Bone Miner Res 32:1761-1772
Zhao, Ning; Nociti Jr, Francisco H; Duan, Peipei et al. (2016) Isolation and Functional Analysis of an Immortalized Murine Cementocyte Cell Line, IDG-CM6. J Bone Miner Res 31:430-442
Duan, Peipei; Bonewald, L F (2016) The role of the wnt/?-catenin signaling pathway in formation and maintenance of bone and teeth. Int J Biochem Cell Biol 77:23-29
Yamamoto, Hiroyuki; Ramos-Molina, Bruno; Lick, Adam N et al. (2016) Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition. Bone 84:120-130
Prideaux, Matthew; Dallas, Sarah L; Zhao, Ning et al. (2015) Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms. PLoS One 10:e0125731
Riquelme, Manuel A; Burra, Sirisha; Kar, Rekha et al. (2015) Mitogen-activated Protein Kinase (MAPK) Activated by Prostaglandin E2 Phosphorylates Connexin 43 and Closes Osteocytic Hemichannels in Response to Continuous Flow Shear Stress. J Biol Chem 290:28321-8
Kamel-ElSayed, Suzan A; Tiede-Lewis, LeAnn M; Lu, Yongbo et al. (2015) Novel approaches for two and three dimensional multiplexed imaging of osteocytes. Bone 76:129-40
Xu, Huiyun; Gu, Sumin; Riquelme, Manuel A et al. (2015) Connexin 43 channels are essential for normal bone structure and osteocyte viability. J Bone Miner Res 30:436-48
Kitase, Y; Lee, S; Gluhak-Heinrich, J et al. (2014) CCL7 is a protective factor secreted by mechanically loaded osteocytes. J Dent Res 93:1108-15

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