The overall goal of this project is to design and implement novel strategies for cartilage repair and treatment of osteoarthritis (OA), leveraging tissue engineering and biological signals inspired by the sugar glucosamine (GlcN). Small molecule stimulation of tissue growth would provide a significant tool for the field of tissue engineering that frequently depends on complex and unstable growth factor proteins as biological signals. Preliminary data and published research from the initial funding period established a window of efficacy where chondrocytes, stem cells, and diseased osteoarthritic cells could be stimulated by GlcN to form more cartilage, with new sugar analogs developed by the Yarema Lab demonstrated an even more potent effect. From the mechanistic perspective, we discovered that certain novel analogs suppressed NF-: B, a molecule important in cartilage disease such as osteoarthritis. Finally, in vitro results were translated to pilot in vivo testing in a rodent model of OA with GlcN injected into joint space improving cartilage structure compared to saline control injections. These findings lay the groundwork for a medicinal chemistry approach to defining new small molecules for precise and effective intervention in tissue engineering for OA and cartilage repair. In this competitive renewal, we propose to investigate the ability of novel sugar analogs, designed by the Yarema Lab, to stimulate tissue growth of normal and osteoarthritic chondrocytes in three dimensional biomaterial scaffolds. For sugars demonstrating a significant stimulation of cartilage tissue growth, the mechanism of action will be evaluated. The sugar analog that demonstrates the greatest stimulation of normal and/or diseased cells will then be applied to a rodent animal model of OA. To accomplish these goals, this renewal application will again combine the expertise of a tissue engineer and a glycobiologist while adding new input from a rheumatologist active in clinical trials for glucosamine, to drive forward and translate this new approach for applying sugars in cartilage repair. Overall, the following specific aims will be pursued:
Specific Aim 1. Evaluate and compare the biological response and cartilage tissue development induced by novel GlcN sugar analogs on normal and osteoarthritis cells cultured in hydrogels.
Specific Aim 2. Determine the mechanism of GlcN and novel GlcN analogs on tissue development.
Specific Aim 3. Translation of GlcN/GlcN analogs to a rodent model of osteoarthritis.

Public Health Relevance

Osteoarthritis is a significant public health challenge with millions of Americans suffering from its debilitating effects on joints. We propose to develop new methods to treat OA and promote new cartilage formation using novel sugar analogs based on the sugar glucosamine.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BST-M (02))
Program Officer
Wang, Fei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Singh, Anirudha; Corvelli, Michael; Unterman, Shimon A et al. (2014) Enhanced lubrication on tissue and biomaterial surfaces through peptide-mediated binding of hyaluronic acid. Nat Mater 13:988-95
Coburn, Jeannine M; Wo, Luccie; Bernstein, Nicholas et al. (2013) Short-chain fatty acid-modified hexosamine for tissue-engineering osteoarthritic cartilage. Tissue Eng Part A 19:2035-44
Sharma, Blanka; Fermanian, Sara; Gibson, Matthew et al. (2013) Human cartilage repair with a photoreactive adhesive-hydrogel composite. Sci Transl Med 5:167ra6
Coburn, Jeannine M; Bernstein, Nicholas; Bhattacharya, Rahul et al. (2013) Differential response of chondrocytes and chondrogenic-induced mesenchymal stem cells to C1-OH tributanoylated N-acetylhexosamines. PLoS One 8:e58899
Reid, Branden; Afzal, Junaid M; McCartney, Annemarie M et al. (2013) Enhanced tissue production through redox control in stem cell-laden hydrogels. Tissue Eng Part A 19:2014-23
Simson, Jacob A; Strehin, Iossif A; Lu, Qiaozhi et al. (2013) An adhesive bone marrow scaffold and bone morphogenetic-2 protein carrier for cartilage tissue engineering. Biomacromolecules 14:637-43
Li, Hanwei; Feng, Felicia; Bingham 3rd, Clifton O et al. (2012) Matrix metalloproteinases and inhibitors in cartilage tissue engineering. J Tissue Eng Regen Med 6:144-54
Hwang, Nathaniel S; Varghese, Shyni; Li, Hanwei et al. (2011) Regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells in PEG-ECM hydrogels. Cell Tissue Res 344:499-509
Elmouelhi, Noha; Aich, Udayanath; Paruchuri, Venkata D P et al. (2009) Hexosamine template. A platform for modulating gene expression and for sugar-based drug discovery. J Med Chem 52:2515-30
Varghese, Shyni; Hwang, Nathaniel S; Canver, Adam C et al. (2008) Chondroitin sulfate based niches for chondrogenic differentiation of mesenchymal stem cells. Matrix Biol 27:12-21

Showing the most recent 10 out of 12 publications