Elizabeth O'Byrne

Novartis, Berna, Bern, Switzerland

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Publications (7)23.55 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).
    Journal of Medicinal Chemistry 05/2009; 52(11):3523-38. · 5.61 Impact Factor
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    ABSTRACT: To examine in vivo time-course changes in macromolecular composition of articular cartilage in two surgical models of osteoarthritis (goat: meniscal transection and cartilage incision; rabbit: medial meniscectomy). Collagen integrity and proteoglycan (PG) content were evaluated in both models by magnetization transfer (MT) and contrast-enhanced MRI, respectively. The MT rate k(m) for the exchange process between the bulk water and water bound to collagen was determined as a marker of the collagen network. Local changes in cartilage fixed charge density, i.e., where PGs are depleted, were derived from T(1) relaxation maps as obtained after an infusion of Gd(DTPA)(2-), a paramagnetic agent. In the goat model, the MT rate constant k(m) was significantly higher at 2 weeks post surgery, a possible sign of cartilage swelling, then decreased below baseline values, most likely indicative of disruption in the collagen framework. Meanwhile, post-Gd(DTPA)(2-) MRI acquisition indicated a significant and sustained loss of PGs. The rabbit model produced milder lesions. Although the difference was non-significant, k(m) steadily decreased in response to the surgical insult while kinetics of Gd(DTPA)(2-) uptake, after reaching a peak level at 6 weeks, were back to normal values after 12 weeks. In the goat model, joint instability and cartilage damage was a permanent trigger for cartilage degeneration producing MRI changes. However, biomechanical stress due to partial medial meniscectomy in knees of mature rabbits produced only mild, focal lesions and PG depletion that was partially reversible. This proof-of-concept study identified MT and T(1) parameters as useful surrogate markers in animal models of osteoarthritis.
    Skeletal Radiology 09/2006; 35(8):555-64. · 1.74 Impact Factor
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    ABSTRACT: Proteoglycan (PG) loss and disruption of the collagen framework in cartilage are early events associated with osteoarthritis (OA). The feasibility of in vivo high-resolution MRI assessments probing both macromolecules was explored in articular cartilage of the rabbit knee. One-millimeter thick coronal images were obtained at 3 T with a 97 x 97 microm(2) pixel size. A 22% decrease in the magnetization transfer (MT) exchange rate along with an approximately 2-fold greater Gd(DTPA)(2-)-induced decrease in T(1) relaxation time were measured in response to papain injection 1 day prior to the MRI session, indicative of an alteration of collagen integrity and PG depletion, respectively. A two-point method was tested as an alternative to the more time-consuming multipoint method typically used to measure T(1) changes. Kinetics of Gd(DTPA)(2-) uptake were observed with a 10-min time resolution. The diffusive transport of Gd(DTPA)(2-) was characterized by a T(1) decrease approximately 2-fold faster in papain-treated knees. These data suggest that kinetics of tracer diffusion may be used as an informative marker of PG loss, in addition to the amplitude of T(1) variations. When applied to a relevant OA model, the combination of MT and Gd(DTPA)(2-)-MRI may help in identifying new active compounds during efficacy studies on cartilage protection.
    Magnetic Resonance in Medicine 10/2003; 50(3):541-9. · 3.27 Impact Factor
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    ABSTRACT: Loss of proteoglycans (PGs) from the extracellular matrix of cartilage is an early event of osteoarthritis. The capability of Gd(DTPA)(2-)-enhanced MRI to quantitatively assess PG content was explored in a goat model of cartilage degeneration. Partial to total PG depletion was induced by an intraarticular injection of papain 1 day prior to the MRI session. A close correlation was found between the extent of the PG loss and the Gd(DTPA)(2-)-induced T(1) decrease. Papain-induced PG depletion was confirmed by post-mortem histological and biochemical assessments. A 2-hr delay after Gd(DTPA)(2-) injection was found to be optimal for an accurate quantitation of the cartilage defect. A series of knee flexions were performed post-Gd(DTPA)(2-) injection to facilitate penetration of the contrast agent into cartilage. However, DeltaT(1)'s observed in cartilage of exercised goat knees were not affected by papain or IL1beta pretreatment. Therefore, as long as a preinjection T(1) map was obtained, the Gd(DTPA)(2-)-enhanced MRI technique provided good sensitivity in detecting partial loss of PG in articular cartilage. This was true only when the animal was maintained in a resting state during diffusion of the Gd(DTPA)(2-). This approach is of particular interest for long-term evaluations of cartilage degeneration and regeneration.
    Magnetic Resonance in Medicine 07/2003; 49(6):1037-46. · 3.27 Impact Factor
  • Elizabeth O'Byrne, Theodore Pellas, Didier Laurent
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    ABSTRACT: The molecular organization and biochemical composition that give cartilage the viscoelasticity necessary for load distribution also convey unique magnetic resonance (MR) properties. In that context, MR imaging has the potential to detect cartilage degeneration and regeneration. Magnetization transfer (MT) imaging probes the exchange of magnetization between the bulk water pool and the water pool bound to macromolecules such as collagen and hence MT may be applied for evaluation of collagen integrity. In addition, Gd(DTPA)(2-)-induced T1 changes have been proposed as a surrogate marker of proteoglycan (PG) loss based on the principle that the paramagnetic agent Gd(DTPA)2- penetrates cartilage to an equilibrium concentration inversely proportional to the negative charge density (i.e. the PG concentration). Results obtained in vivo from MT and Gd(DTPA)(2-)-enhanced MRI acquisitions on the goat knee showed early signs of biochemical changes in response to a papain injection. A dose-dependent effect of papain was observed with both approaches over a wide range of PG depletion (i.e. T1 measurement) and collagen damage (i.e. MT measurement) as confirmed with post-mortem biochemistry and histology. Development of MRI protocols for non-invasive assessment of cartilage will facilitate diagnosis and monitoring of treatment efficacy in the clinic.
    Novartis Foundation symposium 02/2003; 249:190-8; discussion 198-202, 234-8, 239-41.
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    ABSTRACT: Several studies have reported enhanced repair of damaged cartilage following implantation of mesenchymal stem cells (MSCs) into full-thickness cartilage defects suggesting that the cells in the repair tissue were derived from the implant. However, it cannot be excluded that the enhanced tissue repair is derived from host cells recruited to the defect in response to the implant, rather than the re-population of the tissue by the implanted MSCs. Our objective was to study the short-term fate of fluorescently labeled MSCs after implantation into full-thickness cartilage defects in vivo. The fluorescent dye used in our studies did not affect MSC viability or their ability to undergo osteogenic and chondrogenic differentiation in vitro. MSC gelatin constructs were implanted into full-thickness cartilage defects in goats. These cells retained the dye and were detectable by histology and flow cytometry. At intervals spanning 2 weeks post-implantation we observed gradual loss of implanted cells in the defect as well as fragments of gelatin sponge containing labeled MSCs in deep marrow spaces indicating fragmentation, dislodgement and passive migration. Fluorescent labeling enabled us to determine whether the implanted cells were lost during early time points after implantation as well as their spatial orientation throughout the defect. By determining the fate of implanted cells, new biomaterials could be engineered to correct undesirable characteristics. Testing of new biomaterials in short-term in vivo models would provide faster optimization for cell retention needed for successful, long-term cartilage regeneration.
    Biomaterials 02/2002; 23(1):109-19. · 7.60 Impact Factor
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    ABSTRACT: We investigated the role of collagen in the magnetization transfer (MT) effect in contrast to other macromolecules. By means of phantoms made of collagen, chondroitin sulfate (CS) and albumin, MR parameters have been optimized in order to reduce the acquisition time and improve the sensitivity, as well as to minimize the contributions from CS and albumin to the MT induced signal attenuation. The same method was used to study cartilage ex vivo (bovine articular and nasal cartilage plugs) and in vivo (goat knee femoral chondyle). In phantom samples, the MT signal attenuation depended on the collagen concentration while contributions from the other macromolecules were found to be minimal. In average, analysis of MT images revealed a approximately 25%, approximately 35% and approximately 30% signal attenuation in 10% w/v type I collagen gels, cartilage plugs, and cartilage from the weight-bearing areas of the goat knee, respectively. Biochemical data revealed that treatment of cartilage plugs with bacterial collagenase led to collagen depletion and correspondingly to a decrease of the MT response. In contrast, trypsin-induced proteoglycan loss in cartilage plugs did not alter the MT effect. A significant correlation was observed between the collagen content in these plugs and their respective MT ratios and the rate constant k for the exchange process bound versus free water. Finally, data obtained from in vivo MT measurement of the goat knee demonstrated that intra-articular injection of papain might not only cause degradation of proteoglycans but also a change in collagen integrity in a dose-dependent manner. We conclude that in vivo measurement of MT ratios gives quantitative and qualitative information on the collagen status and may be applied for the routine evaluation of normal and abnormal articular cartilage.
    Magnetic Resonance Imaging 01/2002; 19(10):1279-86. · 2.06 Impact Factor