Articular cartilage is a long-lasting, durable tissue that lubricates and redistributes compressive loading in joints. Both of these functions are compromised in cartilage diseases and injuries such as osteoarthritis (OA). A key component of articular cartilage lubrication is superficial zone protein (SZP), which displays altered levels in animal models of early- and late-stage OA. SZP synthesis is mechanically regulated in vivo, and through mechanical stimulation its expression has been manipulated successfully in vitro. Combining these findings with previous successes in manipulating the mechanical properties of engineered cartilage, the long- term mission of the investigators is the complete regeneration of articular cartilage in the joint to restore both the lubrication and mechanical functionality of this tissue. Toward this goal, the hypothesis of this proposal is that cartilage engineered with boundary lubrication and mechanical properties using a combination of growth factors, cytoskeletal modulation, and mechanical signaling can restore articular cartilage in a murine model by maintaining its biological homeostasis and structural integrity.
Three specific aims are proposed: 1) to determine the influence and the mechanism of the biomechanical signaling of hydrostatic pressure on SZP mRNA and protein expression in articular cartilage tissue explants, 2) to engineer lubrication into tissue engineered cartilage using a combination of growth factors, cytoskeletal modulation, and mechanical signaling, and 3) to determine the integrity and stability of lubricated, tissue engineered cartilage in vivo utilizing a SCID mouse model. The successful validation of lubricated, tissue engineered construct functionality the mouse model would lead to larger animal studies and potential clinical translation.

Public Health Relevance

By providing a low friction surface and by distributing load, healthy articular cartilage is responsible for the smooth movement of joints. Cartilage injuries and degeneration result in increased friction and shear stresses being applied directly to bone, leading to inflammation, pain, and disability. Degenerative joint disease and osteoarthritis (OA) affects over 26 million adults in the U.S., and health care costs for treatment of OA in the knee alone are $14 billion per year. Uncovering the mechanisms of joint lubrication will aid in the understanding of degenerative joint disease or osteoarthritis. Engineering new cartilage with lubrication and mechanical properties would result in a functional tissue that could potentially be used to treat damaged and arthritic joints.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR061496-02
Application #
8309190
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2011-08-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$338,889
Indirect Cost
$113,889
Name
University of California Davis
Department
Orthopedics
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Kwon, Heenam; Paschos, Nikolaos K; Hu, Jerry C et al. (2016) Articular cartilage tissue engineering: the role of signaling molecules. Cell Mol Life Sci 73:1173-94
Inui, Atsuyuki; Iwakura, Takashi; Hari Reddi, A (2016) Regulation of lubricin/superficial zone protein by Wnt signalling in bovine synoviocytes. J Tissue Eng Regen Med 10:172-7
Miyatake, Kazumasa; Iwasa, Kenjiro; McNary, Sean M et al. (2016) Modulation of Superficial Zone Protein/Lubricin/PRG4 by Kartogenin and Transforming Growth Factor-β1 in Surface Zone Chondrocytes in Bovine Articular Cartilage. Cartilage 7:388-97
Peng, Gordon; McNary, Sean M; Athanasiou, Kyriacos A et al. (2016) Superficial Zone Extracellular Matrix Extracts Enhance Boundary Lubrication of Self-Assembled Articular Cartilage. Cartilage 7:256-64
Peng, Gordon; McNary, Sean M; Athanasiou, Kyriacos A et al. (2015) The distribution of superficial zone protein (SZP)/lubricin/PRG4 and boundary mode frictional properties of the bovine diarthrodial joint. J Biomech 48:3406-12
Cuellar, Araceli; Reddi, A Hari (2015) Stimulation of Superficial Zone Protein/Lubricin/PRG4 by Transforming Growth Factor-β in Superficial Zone Articular Chondrocytes and Modulation by Glycosaminoglycans. Tissue Eng Part A 21:1973-81
Makris, Eleftherios A; Gomoll, Andreas H; Malizos, Konstantinos N et al. (2015) Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol 11:21-34
Arzi, B; DuRaine, G D; Lee, C A et al. (2015) Cartilage immunoprivilege depends on donor source and lesion location. Acta Biomater 23:72-81
DuRaine, Grayson D; Brown, Wendy E; Hu, Jerry C et al. (2015) Emergence of scaffold-free approaches for tissue engineering musculoskeletal cartilages. Ann Biomed Eng 43:543-54
Murphy, Meghan K; Arzi, Boaz; Prouty, Shannon M et al. (2015) Neocartilage integration in temporomandibular joint discs: physical and enzymatic methods. J R Soc Interface 12:

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