Osteocytes, the most numerous cells in bone, are critical for bone health and bone quality. They are essential for bone to sense and adapt to mechanical stimuli and to remodel damaged tissue. Since osteocytes are completely encased in mineralized bone matrix, their survival and function are entirely dependent on transport of solutes (metabolites, growth factors, cytokines, and other signaling molecules) through the lacunar-canalicular system (LCS). Despite advances in delineating transport pathways in bone, little is known about the mechanisms involved in moving biological molecules to and from osteocytes in vivo. This reflects a lack of methods available to study these questions under real-time conditions in living animals. To this end, we recently developed a new imaging method based on Fluorescence Recovery After Photobleaching (FRAP) that allows measurement of solute movement in the bone LCS in situ and in real-time (Wang et al.,2005. Proc Natl Acad Sci 102:11911). We propose to use this novel approach in combination with mathematical / computational modeling to fully characterize diffusion and convection in bone. To test the hypothesis that convection due to mechanical loading is the primary mechanism for moving large molecules in the LCS, we will first quantify the baseline diffusive transport of solutes of various sizes in post-mortem bones. Convective transport driven by blood pressure and mechanical loading will be subsequently measured in live animals. These studies will delineate the transport mechanisms that are essential for osteocyte viability and bone mechano-transduction, and provide new insights into mass transport in other biological and engineered systems (e.g., tissue engineering scaffolds). Detailed knowledge of how molecules move within bone will help define molecular parameters such as hydrodynamic radii and half-life times for new drugs so that they can be delivered effectively into bone to treat diseases such as osteoporosis and arthritis.
Our specific aims are: 1) to determine how solute diffusion in the bone LCS depends on the solute's molecular weight;2) to determine how solute transport in the bone LCS is affected by vascular pressure;3) to determine how solute transport in the bone LCS is affected by mechanical loading.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054385-05
Application #
8125096
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2007-09-15
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$306,381
Indirect Cost
Name
University of Delaware
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Martinez, Jerahme R; Grindel, Brian J; Hubka, Kelsea M et al. (2018) Perlecan/HSPG2: Signaling role of domain IV in chondrocyte clustering with implications for Schwartz-Jampel Syndrome. J Cell Biochem :
Zhang, Bingbing; Hou, Rutao; Zou, Zhen et al. (2018) Mechanically induced autophagy is associated with ATP metabolism and cellular viability in osteocytes in vitro. Redox Biol 14:492-498
Wang, Bin; Sun, Xuanhao; Akkus, Ozan et al. (2018) Elevated solute transport at sites of diffuse matrix damage in cortical bone: Implications on bone repair. J Orthop Res 36:692-698
Wang, Liyun (2018) Solute Transport in the Bone Lacunar-Canalicular System (LCS). Curr Osteoporos Rep 16:32-41
Lv, Mengxi; Zhou, Yilu; Chen, Xingyu et al. (2018) Calcium signaling of in situ chondrocytes in articular cartilage under compressive loading: Roles of calcium sources and cell membrane ion channels. J Orthop Res 36:730-738
Shoga, Janty S; Graham, Brian T; Wang, Liyun et al. (2017) Direct Quantification of Solute Diffusivity in Agarose and Articular Cartilage Using Correlation Spectroscopy. Ann Biomed Eng 45:2461-2474
Chiu, Yu-Chieh; Fong, Eliza L; Grindel, Brian J et al. (2016) Sustained delivery of recombinant human bone morphogenetic protein-2 from perlecan domain I - functionalized electrospun poly (?-caprolactone) scaffolds for bone regeneration. J Exp Orthop 3:25
Fan, Lixia; Pei, Shaopeng; Lucas Lu, X et al. (2016) A multiscale 3D finite element analysis of fluid/solute transport in mechanically loaded bone. Bone Res 4:16032
Wijeratne, Sithara S; Martinez, Jerahme R; Grindel, Brian J et al. (2016) Single molecule force measurements of perlecan/HSPG2: A key component of the osteocyte pericellular matrix. Matrix Biol 50:27-38
Srinivasan, Padma P; Parajuli, Ashutosh; Price, Christopher et al. (2015) Inhibition of T-Type Voltage Sensitive Calcium Channel Reduces Load-Induced OA in Mice and Suppresses the Catabolic Effect of Bone Mechanical Stress on Chondrocytes. PLoS One 10:e0127290

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