Articular cartilage injury and degeneration are leading causes of disability [1, 2]. Accessing bone marrow cells for cartilage repair through microfracture is commonly performed clinically. However, the frequently fibrous repairs yield mixed results [3, 4]. Safe, localized in vivo use of bioactive factors to improve chondrogenesis in situ of human bone marrow cells (BMC) for cartilage repair therefore has compelling public health impacts. Transforming growth factor-beta-1 (TGF-b1) consistently induces chondrogenesis of hBMC [5, 6]. Major challenges for in vivo administration of TGF-b1 include controlling and containing TGF-b1 effects. TGF-b signaling through its type II receptor (TbR-ll) is important to cellular responsiveness to TGF-b and to cartilage homeostasis [7]. Using chondrogenesis as the desired endpoint, we propose to study an intriguing question as to whether the pattern of TbR-II expression, in particular sustained TbR-II expression, is the mechanism that determines whether bone marrow cells will undergo chondroid differentiation in vivo. The central hypothesis of this proposal is that sustained upregulation of TbR-ll is necessary for in vivo chondrogenesis of bone marrow cells and that this can be achieved through sustained administration of TGF-B1.
The specific aims of this proposal are: 1. To test the hypothesis that sustained upregulation of TbR-II is necessary for chondrogenesis of adult human BMC in vivo, within the diarthrodial environment. 2. To test the hypothesis that controlled release of TGF-b1 from genipin crosslinked polyethylene glycol (PEG-genipin) scaffolds will induce localized, sustained in vivo TbR-ll upregulation, chondrogenesis of host bone marrow cells (BMC), and improve osteochondral repair with minimal joint effects. 3. To test the hypothesis that highly localized, stable and regulatable TGF-b1 gene expression in diarthrodial joints can be achieved by adeno-associated virus (AAV)-TGF-b vectors that are gradually released from PEG-genipin scaffolds. Such gene expression is anticipated to induce localized in vivo upregulation of TbR-ll, chondrogenesis of host bone marrow repair cells, and improve osteochondral repair with minimal joint effects. The unique translational aspects of this proposal include (1) a Clinician-Scientist led multidisciplinary team to optimize related but independent strategies for localized, controlled in vivo delivery of growth factors to improve the cartilage repair potential of bone marrow cells; and (2) provision of a direct pathway for clinical translation of innovative scaffold technology and controlled gene therapy to improve cartilage repair, and the arthroscopic use of novel nondestructive advanced cartilage imaging technologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR051963-06
Application #
8799194
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2007-08-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2011
Total Cost
$44,520
Indirect Cost
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Williams, Ashley; Winalski, Carl S; Chu, Constance R (2017) Early articular cartilage MRI T2 changes after anterior cruciate ligament reconstruction correlate with later changes in T2 and cartilage thickness. J Orthop Res 35:699-706
LaPrade, Robert F; Dragoo, Jason L; Koh, Jason L et al. (2016) AAOS Research Symposium Updates and Consensus: Biologic Treatment of Orthopaedic Injuries. J Am Acad Orthop Surg 24:e62-78
Goodrich, Laurie R; Chen, Albert C; Werpy, Natasha M et al. (2016) Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects: Does It Enhance Repair? J Bone Joint Surg Am 98:23-34
Chu, Constance R (2015) The Challenge and the Promise of Bone Marrow Cells for Human Cartilage Repair. Cartilage 6:36S-45S
Chu, Constance R; Millis, Michael B; Olson, Steven A (2014) Osteoarthritis: From Palliation to Prevention: AOA Critical Issues. J Bone Joint Surg Am 96:e130
Braun, Hillary J; Kim, Hyeon Joo; Chu, Constance R et al. (2014) The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy. Am J Sports Med 42:1204-10
Grissom, Murray J; Temple-Wong, Michele M; Adams, Matthew S et al. (2014) Synovial Fluid Lubricant Properties are Transiently Deficient after Arthroscopic Articular Cartilage Defect Repair with Platelet-Enriched Fibrin Alone and with Mesenchymal Stem Cells. Orthop J Sports Med 2:
Chu, Constance R; Williams, Ashley A; West, Robin V et al. (2014) Quantitative Magnetic Resonance Imaging UTE-T2* Mapping of Cartilage and Meniscus Healing After Anatomic Anterior Cruciate Ligament Reconstruction. Am J Sports Med 42:1847-56
Lee, Hannah H; O'Malley, Michael J; Friel, Nicole A et al. (2013) Effects of doxycycline on mesenchymal stem cell chondrogenesis and cartilage repair. Osteoarthritis Cartilage 21:385-393
Qian, Yongxian; Williams, Ashley A; Chu, Constance R et al. (2013) Repeatability of ultrashort echo time-based two-component T2* measurements on cartilages in human knee at 3 T. Magn Reson Med 69:1564-72

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