PTH(1-34) Protects Against Articular Cartilage Degeneration Following Meniscal/ligamentous Injury in a Mouse Model of Osteoarthritis
Category: Disorders of Bone and Mineral Metabolism (Genetic, Basic, and Trans.)
Oral Presentations, Presentation Number: 1015
Session: Concurrent Oral Session 03: Disorders of Bone and Mineral Metabolism I: Treatments
Saturday, September 12, 2009 10:30 AM - 10:45 AM, Colorado Convention Center, Room 108-112
* Erik Sampson, University of Rochester, USA, Todd O'Brien, Department of Orthopaedics, USA, Hani Awad, Department of Biomedical Engineering, USA, Di Chen, Rush University Medical Center, USA, Edward Schwarz, University of Rochester, USA, Susan Bukata, UCLA, USA, J. Edward Puzas, University of Rochester School of Medicine, USA, Regis O'Keefe, University of Rochester, USA, Michael Zuscik, University of Rochester School of Medicine & Dentistry, USA, Randy Rosier, University of Rochester Medical Center, USA
Osteoarthritis (OA) is a degenerative joint disease projected to afflict >50 million Americans by 2020. Not only is the mechanism of pathogenesis not known, but the only existing therapies for OA are palliative: steroidal or non-steroidal anti-inflammatory agents. Since the articular chondrocyte is essential for maintaining joint cartilage and its endochondral ossification-like maturation is associated with OA in general, pathways that inhibit this inappropriate maturation represent candidate therapeutic targets. Related to this, it is established that i) PTH and PTHrP are potent inhibitors of chondrocyte maturation, ii) PTH receptor type 1 (PTHR1) is up-regulated in articular chondrocytes during human OA, and iii) activation of PTHR1 induces chondrocyte matrix synthesis and proliferation. Based on this, we have hypothesized that PTH will inhibit the aberrant articular chondrocyte maturation that occurs in OA and prevent/delay the associated degeneration of the articular cartilage. To test this hypothesis, we employed a mouse model of knee OA involving disruption of the medial meniscus and the medial collateral ligament (ML injury). The impact of systemic administration of PTH(1-34) on the progression of OA in this model was examined. First, using quantitative PCR, we confirmed that PTHR1 is induced 5-fold in articular cartilage 8 weeks following ML injury. We next performed ML injury or sham surgery on mice and then began systemic treatment with saline or PTH(1-34) (40 μg/kg/day, intraperitoneal injection) either immediately or 8 weeks after surgical induction of the injury. Mice were sacrificed at 4, 8, or 12 weeks post-surgery and joints were harvested for μCT and histologic analyses. μCT revealed increased bone volume in joints from PTH(1-34)-treated mice, confirming the bone anabolic effect of the treatments. After 12 weeks of PTH(1-34) treatment, there was 20-27% more articular cartilage compared to saline-treated mice, as determined by histomorphometry. Strikingly, delayed administration of PTH(1-34) was equally if not more effective in protecting against degeneration, with 31-35% more cartilage in the treated groups. These pre-clinical findings provide strong proof-of-concept support for the use of teriparatide to decelerate articular cartilage degeneration in OA patients and delay the onset of morbidities associated with end-stage disease.
* Presenting Authors(s): Erik Sampson, University of Rochester, USA