By the simplest account, osteoarthritis is the wearing away of articular cartilage, a tissue that has a limitedability to repair itself. As a result, minor damage from load injury or joint inflammation can lead toprogressive matrix degradation. Recent studies found significant increases of degraded matrix in thesynovial fluid of injured joints along with a surge of degradative enzymes, called metalloproteinases (MMPs).Of particular interests are MMP-2 and MMP-9, which are well known for their roles in angiogenesis and formediating cell migration during joint inflammation in addition to degrading cartilage matrix. Studying theroles of MMP-2 and MMP-9 in vivo is complicated, however, due to various degrees of injury, the complianceof soft tissues, and, sometimes, an alteration of joint kinematics. Taking advantage of an injury model, wecan induce defined cartilage injury in a mouse knee without alterating joint kinematics. We propose to testthe hypothesis that elevation of MMP-2 and MMP-9 mediates acute joint inflammation and increasescartilage degeneration after load injury with the following two specific aims: 1) To determine whether injuryinducedcartilage degeneration in MMP-2 or MMP-9 knockout mice is decreased as compared to wildtypes;2) To determine whether injury-induced cartilage degeneration in MMP-9 knockout and wildtype miceincreases with the treatment of recombinant MMP-9 protein. The outcomes will be tested at molecular,cellular, and tissue levels with a focus on matrix degradation and evaluation of joint inflammation bydetermining proteoglycan content/degradation, collagen cleavage, enzyme content (MMP-1, -2, -3, -9, -13;aggrecanases; TIMP-1, -2, -3;), inflammation (IL-1, IL-6, TNF-a, synovial membrane) and proteinaseactivities using FTIR spectroscopy, contrast-enhanced micro-computed tomography, immunohistochemistryand in situ zymography. The functional properties of cartilage will be determined using micro-indentationtests. These outcome measurements will depend heavily on the Analytical Microscopy Core and ImagingCore. This project will also enable us to establish a novel mouse model for future studies of signal pathwaysand molecules related to MMP-2 and MMP-9 and/or important to cartilage degradation, such as MMP-13,aggrecanase, IL-1, and TNF-a. Ultimately, increased understanding of the mechanisms of cartilagedegeneration after injury will enable more specific targeting of therapeutics for osteoarthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
2P30AR046121-06A1
Application #
7145970
Study Section
Special Emphasis Panel (ZAR1-YZW-H (O2))
Project Start
2006-03-01
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
6
Fiscal Year
2006
Total Cost
$86,768
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
Qu, Dovina; Subramony, Siddarth D; Boskey, Adele L et al. (2017) Compositional mapping of the mature anterior cruciate ligament-to-bone insertion. J Orthop Res 35:2513-2523
Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere et al. (2017) Bone regeneration in critical bone defects using three-dimensionally printed ?-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2. J Biomed Mater Res B Appl Biomater 105:366-375
Yang, Haisheng; Albiol, Laia; Chan, Wing-Lee et al. (2017) Examining tissue composition, whole-bone morphology and mechanical behavior of GorabPrx1 mice tibiae: A mouse model of premature aging. J Biomech 65:145-153
Foster, B L; Kuss, P; Yadav, M C et al. (2017) Conditional Alpl Ablation Phenocopies Dental Defects of Hypophosphatasia. J Dent Res 96:81-91
Mediero, Aránzazu; Wilder, Tuere; Ramkhelawon, Bhama et al. (2016) Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. FASEB J 30:3835-3844
Mediero, Aránzazu; Ramkhelawon, Bhama; Wilder, Tuere et al. (2016) Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis. Ann Rheum Dis 75:1706-13
Mediero, Aránzazu; Wilder, Tuere; Reddy, Vishnu S R et al. (2016) Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. FASEB J 30:3887-3900
Masci, Marco; Wang, Min; Imbert, Laurianne et al. (2016) Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta. Bone 87:120-9
Holyoak, Derek T; Tian, Ye F; van der Meulen, Marjolein C H et al. (2016) Osteoarthritis: Pathology, Mouse Models, and Nanoparticle Injectable Systems for Targeted Treatment. Ann Biomed Eng 44:2062-75
Morgan, Timothy G; Bostrom, Mathias P G; van der Meulen, Marjolein C H (2015) Tissue-level remodeling simulations of cancellous bone capture effects of in vivo loading in a rabbit model. J Biomech 48:875-82

Showing the most recent 10 out of 195 publications