Future Directions

1. Future Directions Steven Abramson M.D. NYU Langone Medical Center

2. Future Directions: 3-10 Year Horizon Improved analgesics Structure modification (DMOADs) Clinical and pathogenic phenotyping Imaging and biochemical markers Genetic susceptibility for incident and progressive disease Minimally invasive surgical advances Tissue repair

3. Future 1: Biomarkers: Focus on Detecting and Treating Early Molecular Stages of Osteoarthritis Biomarker Endpoints Defining Structural Outcomes X-RAY MRI Ultrasound Bone Scintigraphy BIOMARKERS Pain MOLECULAR PRERADIOGRAPHIC RADIOGRAPHIC JOINT REPLACEMENT Prevention Defining Disease State Devices (Courtesy of V. Kraus)

4. A B 100 ms 0 Proteoglycan Loss in Early Osteoarthritis T1=68±4ms (R. Regatte, NYUHJD, unpublished data)

5. OA is condition of heterogeneous etiologies …which develops over decades Future 2: OA Phenotypes

7. OA “Phenotype”: Understanding Early Molecular Mechanisms Aging processes Genetic susceptibility Mechano-transduction Cartilage Biology Bone biology Synovial events Metabolic events

8. OA Phenotype & Disease Mechanisms Primary Post-traumatic Metabolic Age related CCPD Kashin-Beck Disease (?) Estrogen Genetics Biomechanics Catabolic State OA Rx Progression

9. Importance of OA Phenotypes in Early Osteoarthritis Mitochondria, AGE, Aspartate, SirT1 Aging ADAMTS, MMP-13, DDR2, NO Cartilage BMP, VEGF, RANKL, Wnt, TGFb Bone IL-1, IL-1RN, COX-2, TNFa Inflammation Adipokines, estrogen, oxLDL Metabolic RX RX RX

10. Future 3: Treating the Whole Joint BML Bone marrow lesion Subchondral cyst Synovial thickening, Effusion Krasnokutsky, Samuels, et al

11. Mechanisms Recently Targeted in Drug Development • MMP/aggrecanase inhibitors • Agg-523 (Wyeth, Phase I) • IL-1 antagonist • AMG-108 (Amgen, Phase II) • iNOS Inhibitor • SD6010 (Pfizer, Phase III) • NSAID plus PPI (Astrazeneca) • NSAID plus NO (NicOx) • Icatibant (Bradykinin B2 antagonist peptide) (Sanofi-Aventis, Phase II) • a-NGF ab Rinat 624 (Pfizer, Phase III) DMOAD Pain

12. Regulation of Osteoblast and Osteoclast Activation in the Treatment of Osteoarthritis? DMOADs? Bisphosphonate Calcitonin Strontium Cathepsin K

13. EMERGING AREAS Genetics Intra-articular therapy Tissue Engineering

14. Intra-articular drug delivery Tissue-specific delivery Circumvent systemic toxicity Visco-supplements Hyaluronic acid Lubricin Stimulators of ECM synthesis Small molecules Biologicals Cells and or engineered cells Inhibitors of ECM degradation Inflammation Glucocorticoids

15. Gene therapy for cartilage repair Chondrocytes Engineered cell cDNA Growth factors: BMPs, IGFs, FGFs Transcription factors: Sox9, Sox6 Signal transduction: Smads Viral Engineered cell MSCs

16. Future 4. Role of Genetics in OA Genetic variations will influence OA: Phenotype Susceptibility Severity Rate of progression

17. Valdes and Spector, 2009; Med. Clin. N. Am 93:45-66

18. Valdes and Spector, 2009; Med. Clin. N. Am 93:45-66

19. Summary: Future Directions OA pain - safe, more effective analgesia Genetic and biochemical determination of risk for progression Functional imaging studies of disease activity Molecular targeting for early intervention Microsurgical intervention Cellular tissue repair