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The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling

Zhao, Yun-Peng; Tian, Qing-Yun; Frenkel, Sally; Liu, Chuan-Ju
Endochondral ossification plays a key role in the bone healing process, which requires normal cartilage callus formation. Progranulin (PGRN) growth factor is known to enhance chondrocyte differentiation and endochondral ossification during development, yet whether PGRN also plays a role in bone regeneration remains unknown. In this study we established surgically-induced bone defect and ectopic bone formation models based on genetically-modified mice. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology and immunohistochemistry. PGRN deficiency delayed bone healing, while recombinant PGRN enhanced bone regeneration. Moreover, PGRN was required for BMP-2 induction of osteoblastogenesis and ectopic bone formation. Furthermore, the role of PGRN in bone repair was mediated, at least in part, through interacting with TNF-alpha signaling pathway. PGRN-mediated bone formation depends on TNFR2 but not TNFR1, as PGRN promoted bone regeneration in deficiency of TNFR1 but lost such effect in TNFR2 deficient mice. PGRN blocked TNF-alpha-induced inflammatory osteoclastogenesis and protected BMP-2-mediated ectopic bone formation in TNF-alpha transgenic mice. Collectively, PGRN acts as a critical mediator of the bone healing process by constituting an interplay network with BMP-2 and TNF-alpha signaling, and this represents a potential molecular target for treatment of fractures, especially under inflammatory conditions.
PMID: 23746860
ISSN: 0142-9612
CID: 394052

Adenosine A2A Receptor Activation Prevents Wear Particle-Induced Osteolysis

Mediero, Aranzazu; Frenkel, Sally R; Wilder, Tuere; He, Wenjie; Mazumder, Amitabha; Cronstein, Bruce N
Prosthesis loosening, associated with wear particle-induced inflammation and osteoclast-mediated bone destruction, is a common cause for joint implant failure, leading to revision surgery. Adenosine A(2A) receptors (A(2A)Rs) mediate potent anti-inflammatory effects in many tissues and prevent osteoclast differentiation. We tested the hypothesis that an A(2A)R agonist could reduce osteoclast-mediated bone resorption in a murine calvaria model of wear particle-induced bone resorption. C57BL/6 and A(2A)R knockout (A(2A)R KO) mice received ultrahigh-molecular weight polyethylene particles and were treated daily with either saline or the A(2A)R agonist CGS21680. After 2 weeks, micro-computed tomography of calvaria demonstrated that CGS21680 reduced particle-induced bone pitting and porosity in a dose-dependent manner, increasing cortical bone and bone volume compared to control mice. Histological examination demonstrated diminished inflammation after treatment with CGS21680. In A(2A)R KO mice, CGS21680 did not affect osteoclast-mediated bone resorption or inflammation. Levels of bone resorption markers receptor activator of nuclear factor kappaB (RANK), RANK ligand, cathepsin K, CD163, and osteopontin were reduced after CGS21680 treatment, together with a reduction in osteoclasts. Secretion of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha was significantly decreased, whereas IL-10 was markedly increased in bone by CGS21680. These results in mice suggest that site-specific delivery of an adenosine A(2A)R agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery.
PMID: 22623741
ISSN: 1946-6234
CID: 167513

The BioDigital Human: A Web-based 3D Platform for Medical Visualization and Education

Qualter, John; Sculli, Frank; Oliker, Aaron; Napier, Zachary; Lee, Sabrina; Garcia, Julio; Frenkel, Sally; Harnik, Victoria; Triola, Marc
NYU School of Medicine's Division of Educational Informatics in collaboration with BioDigital Systems LLC (New York, NY) has created a virtual human body dataset that is being used for visualization, education and training and is accessible over modern web browsers.
PMID: 22357018
ISSN: 0926-9630
CID: 157490

The efficacy of intra-articular hyaluronan injection after the microfracture technique for the treatment of articular cartilage lesions

Strauss, Eric; Schachter, Aaron; Frenkel, Sally; Rosen, Jeffrey
BACKGROUND: Although the exact mechanism of action has yet to be elucidated, recent animal studies have demonstrated chondroprotective and anti-inflammatory properties of hyaluronic acid viscosupplementation. HYPOTHESIS: Intra-articular hyaluronic acid after microfracture improves the quality of the repair leading to a more hyaline-like repair tissue with better defect fill and adjacent area integration. STUDY DESIGN: Controlled laboratory study. METHODS: Full-thickness cartilage defects were created in the weightbearing area of the medial femoral condyle in 36 female New Zealand White rabbits. The defects were then treated with surgical microfracture. Eighteen rabbits formed the 3-month cohort and the other 18 formed the 6-month cohort. Within each cohort, 6 rabbits were randomly assigned to receive 3 weekly injections of hyaluronic acid (group A), 5 weekly injections (group B), or control injections of normal saline (group C). At 3 and 6 months postmicrofracture, the animals were sacrificed and the operative knee harvested. Repair tissue was assessed blinded- both grossly, using a modified component of the International Cartilage Repair Society (ICRS) Cartilage Repair Assessment scoring scale, and histologically, using the modified O'Driscoll histological cartilage scoring system. Comparisons were made with respect to gross and histologic findings between treatment groups at each time point. Effects of each treatment type were also evaluated longitudinally by comparing the 3-month results with the 6-month results. Statistical analysis was performed using unpaired Student t tests with significance defined as P < .05. RESULTS: At 3 months, gross and histologic evaluation of the repair tissue demonstrated that the 3-injection group had significantly better fill of the defects and more normal appearing, hyaline-like tissue than controls (a mean ICRS score of 1.92 vs 1.26; P < .05 and a mean modified O'Driscoll score of 10.3 vs 7.6; P < .02). Specimens treated with 5 weekly injections were not significantly improved compared with controls. At 6 months, the mean gross appearance and histologic scores between the 3 specimen cohorts were not significantly different. However, examination of the entire operative knee demonstrated a significantly greater extent of degenerative changes (synovial inflammation and osteophyte formation) in the control group than in both hyaluronic acid treatment groups (P < .05). CONCLUSION: Supplementing the microfracture technique with 3 weekly injections of intra-articular hyaluronic acid had a positive effect on the repair tissue that formed within the chondral defect at the early follow-up time point. This improvement was not found for the 3-injection group at 6 months or for the 5-injection group at either time point. Additionally, hyaluronic acid supplementation had a possible chondroprotective and anti-inflammatory effect, limiting the development of degenerative changes within the knee joint. CLINICAL RELEVANCE: The adjunctive use of hyaluronic acid appears to hold promise in the treatment of chondral injuries and warrants further investigation
PMID: 19204370
ISSN: 1552-3365
CID: 100949

Regional gene therapy for full-thickness articular cartilage lesions using naked DNA with a collagen matrix

Di Cesare, Paul E; Frenkel, Sally R; Carlson, Cathy S; Fang, Carrie; Liu, Chuanju
A novel gene therapy approach for treating damaged cartilage is proposed that involves placing endotoxin-free cDNA containing the gene for bone morphogenetic protein-2 (BMP-2) in type I collagen sponges and then transferring the naked plasmid DNA construct to the injury site. A full-thickness cartilaginous defect in rabbits implanted with plasmid containing a marker gene (beta-galactosidase) showed expressed protein as detected by immunostaining. At 1 week postimplantation, mesenchymal cells subjacent to the defect had incorporated the implanted naked plasmid DNA and, once transfected, served as local bioreactors, transiently producing the gene product. Plasmids containing the gene for BMP-2 implanted in collagen sponges in cartilage lesions stimulated hyalinelike articular cartilage repair at 12 weeks postimplantation, nearly equivalent in quality to that induced by collagen sponges with recombinant BMP-2 protein. Our approach circumvents the risks of inflammation and immunogenic response associated with the use of viral vectors. Naked plasmid DNA as a vehicle for transferring therapeutic genes has been shown to be effective in a therapeutic model within rabbit articular cartilage and appears to be safe and cost effective.
PMID: 16609967
ISSN: 0736-0266
CID: 159234

Virtual Prosections: Head & Neck Volume 1

Harnik, Victoria; Frenkel, Sally
[New York] : NYUSOM Digital Press (Institute for Innovations in Medical Education), 2015
Extent: 39 p.
CID: 2172282

Virtual Prosections: The Pelvis & Perineum

Harnik, Victoria; Frenkel, Sally
[New York] : NYUSOM Digital Press (Institute for Innovations in Medical Education), 2015
Extent: 33 p.
CID: 2172312

Virtual Prosections: The Upper Limb

Harnik, Victoria; Frenkel, Sally
[New York] : NYUSOM Digital Press (Institute for Innovations in Medical Education), 2015
Extent: 38 p.
CID: 2172322

Virtual Prosections: Head & Neck Volume 2

Harnik, Victoria; Frenkel, Sally
[New York] : NYUSOM Digital Press (Institute for Innovations in Medical Education), 2015
Extent: 43 p.
CID: 2172292

Virtual Prosections: The Abdomen Volume 2

Harnik, Victoria; Frenkel, Sally
[New York] : NYUSOM Digital Press (Institute for Innovations in Medical Education), 2015
Extent: 33 p.
CID: 2172332