Current standards of care for cartilage injuries cannot reliably provide sustained clinical improvement, so there is much interest in the development of alternative, biological approaches towards repair/regeneration. Regenerative medicine approaches typically involve the recruitment or transplantation of endogenous mesenchymal progenitor cells (MFCs) to the defect site. Under controlled conditions, these cells have the potential to proliferate, differentiate along the relevant musculoskeletal lineage and regenerate damaged tissue matrix. However, the intra-articular environment can be hostile to chondrogenesis;specifically, inflammation within the injured joint can inhibit tissue regeneration. Joint inflammation is mediated locally by cytokines such as interleukin-1 and tumor necrosis factor-a. Although proinflammatory cytokines play an important role in the pathogenesis of osteoarthritis, little is known about how they affect cartilage repair strategies involving MFCs. The central hypothesis shaping this project is that inflammation secondary to joint trauma or subsequent surgical intervention can inhibit the regenerative activity of MFCs within the cartilage defect, thus limiting repair. During the mentored phase, a toolset of reporter constructs were developed for monitoring the state of human MFC differentiation, using these constructs to non-invasively track inflammatory and chondrogenic activity within an immunocompromised rat model of cartilage injury. Upon transition to the independent phase of the project, tools developed during the mentored phase will help characterize the proinflammatory environment resulting from surgically-induced joint trauma, identifying factors that impair chondrogenesis and defect repair. Both immunologically-competent and -incompetent animal models of joint injury will be used to determine the ability of MFCs to repair/regenerate cartilage when protected from the identified factors. At the end of this project period, we will have a better understanding of how the joint environment - particularly inflammatory signaling - impacts the ultimate success of cartilage regeneration strategies using heterogeneous progenitor cell populations.

Public Health Relevance

; Because articular cartilage has very limited capacity for self-repair, injuries following trauma persist and can ultimately lead to osteoarthritis (OA). The resulting pain and reduced range of joint motion can severely impair quality of life. The studies described in this proposal should add to our understanding of factors that limit cell-based cartilage repair. Overcoming these factors will help improve repair outcomes and reduce the incidence of post-traumatic OA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Transition Award (R00)
Project #
5R00AR057105-03
Application #
8333207
Study Section
Special Emphasis Panel (NSS)
Program Officer
Wang, Fei
Project Start
2009-07-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$246,974
Indirect Cost
$105,896
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215