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 #
5R01AR054385-06
Application #
8303034
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Sharrock, William J
Project Start
2007-09-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2012
Total Cost
$306,381
Indirect Cost
$106,132
Name
University of Delaware
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Lai, Xiaohan; Price, Christopher; Lu, Xin Lucas et al. (2014) Imaging and quantifying solute transport across periosteum: implications for muscle-bone crosstalk. Bone 66:82-9
Gong, Xiaoyuan; Yang, Weidong; Wang, Liyun et al. (2014) Prostaglandin E2 modulates F-actin stress fiber in FSS-stimulated MC3T3-E1 cells in a PKA-dependent manner. Acta Biochim Biophys Sin (Shanghai) 46:40-7
Lowe, Dylan A; Lepori-Bui, Nadia; Fomin, Peter V et al. (2014) Deficiency in perlecan/HSPG2 during bone development enhances osteogenesis and decreases quality of adult bone in mice. Calcif Tissue Int 95:29-38
Wang, Bin; Lai, Xiaohan; Price, Christopher et al. (2014) Perlecan-containing pericellular matrix regulates solute transport and mechanosensing within the osteocyte lacunar-canalicular system. J Bone Miner Res 29:878-91
Jing, Da; Baik, Andrew D; Lu, X Lucas et al. (2014) In situ intracellular calcium oscillations in osteocytes in intact mouse long bones under dynamic mechanical loading. FASEB J 28:1582-92
Wang, Bin; Zhou, Xiaozhou; Price, Christopher et al. (2013) Quantifying load-induced solute transport and solute-matrix interaction within the osteocyte lacunar-canalicular system. J Bone Miner Res 28:1075-86
Pan, Jun; Wang, Bin; Li, Wen et al. (2012) Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints. Bone 51:212-7
Baro, Vincent J; Bonnevie, Edward D; Lai, Xiaohan et al. (2012) Functional characterization of normal and degraded bovine meniscus: rate-dependent indentation and friction studies. Bone 51:232-40
Bonnevie, E D; Baro, V J; Wang, L et al. (2012) Fluid load support during localized indentation of cartilage with a spherical probe. J Biomech 45:1036-41
Price, Christopher; Zhou, Xiaozhou; Li, Wen et al. (2011) Real-time measurement of solute transport within the lacunar-canalicular system of mechanically loaded bone: direct evidence for load-induced fluid flow. J Bone Miner Res 26:277-85

Showing the most recent 10 out of 26 publications