Intercellular communication is essential for homeostatic function of most organs, to coordinate events during development, and to pace contractions in the heart, lungs, gut, erectile tissue and uterus. Published reports from the principal investigator's group now indicate that coordination of cellular activities through gap junctions is vital in flexor tendons in response to mechanical load and wounding. Exercise is critical to health maintenance: normal activity is positive, immobilization is negative and overactivity is destructive. In medicine, motion therapy post-injury is essential to recover range of motion. The applicants hypothesize that coordination of cellular activities through gap junctions is vital in response to mechanical load and after tendon injury. If gap junctions are blocked, cell coordination will be prevented.
In Specific Aim 1, they will test the importance of gap junctions in signaling via Ca2+, gap junction translocation with a GFP-cx43 construct, and DNA and collagen synthesis in cells that have been mechanically loaded and wounded in vitro +/- gap junction blockage. Loading will include both acute and adaptive regimens.
In Specific Aim 2, they will test the effect of PKC modulation on gap junction expression and function with compounds, such as ATP and norepinephrine, which regulate gap junction signaling and expression.
In Specific Aims 3 and 4, they will conduct similar experiments to those in Aims 1 and 2, but in whole tendon, in response to adaptive loading for up to 5 days. Connexin 43 is a mechanical load-sensitive gene. Knowledge of how tendon cells transduce and respond to mechanical load and wound signals will have impact on our understanding of how patients respond to motion therapy post-injury. Knowledge of how motion acts at the mechanistic level may lead to drug strategies for upregulating cell division and matrix expression with or without motion in aged or disabled patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR038121-12
Application #
6511683
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Panagis, James S
Project Start
1987-08-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
12
Fiscal Year
2002
Total Cost
$217,394
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Orthopedics
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Wall, Michelle E; Otey, Carol; Qi, Jie et al. (2007) Connexin 43 is localized with actin in tenocytes. Cell Motil Cytoskeleton 64:121-30
Wall, Michelle E; Weinhold, Paul S; Siu, Tung et al. (2007) Comparison of cellular strain with applied substrate strain in vitro. J Biomech 40:173-81
Qi, Jie; Chi, Liqun; Faber, James et al. (2007) ATP reduces gel compaction in osteoblast-populated collagen gels. J Appl Physiol 102:1152-60
Qi, Jie; Chi, Liqun; Maloney, Melissa et al. (2006) Interleukin-1beta increases elasticity of human bioartificial tendons. Tissue Eng 12:2913-25
Qi, Jie; Fox, Ann Marie; Alexopoulos, Leonidas G et al. (2006) IL-1beta decreases the elastic modulus of human tenocytes. J Appl Physiol 101:189-95
Jones, Bertina F; Wall, Michelle E; Carroll, R Lloyd et al. (2005) Ligament cells stretch-adapted on a microgrooved substrate increase intercellular communication in response to a mechanical stimulus. J Biomech 38:1653-64
Tsuzaki, M; Bynum, D; Almekinders, L et al. (2005) Mechanical loading stimulates ecto-ATPase activity in human tendon cells. J Cell Biochem 96:117-25
Wall, Michelle E; Faber, James E; Yang, Xi et al. (2004) Norepinephrine-induced calcium signaling and expression of adrenoceptors in avian tendon cells. Am J Physiol Cell Physiol 287:C912-8
Tsuzaki, M; Bynum, D; Almekinders, L et al. (2003) ATP modulates load-inducible IL-1beta, COX 2, and MMP-3 gene expression in human tendon cells. J Cell Biochem 89:556-62
Yamazaki, Satoru; Weinhold, Paul S; Graff, Ronald D et al. (2003) Annulus cells release ATP in response to vibratory loading in vitro. J Cell Biochem 90:812-8

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