artigo sobre teriparatide e artrose

Parathyroid Hormone (1-34) Protects Against Articular Cartilage Degeneration Following Meniscal/ligamentous Injury in a Mouse Model of Osteoarthritis

 

E.S. Sampson*1, T. O’Brien1, H. Awad2, D. Chen1, S. Bukata1, J.E. Puzas1, R.J. O’Keefe1, M.J. Zuscik1 and R.N. Rosier1

 

Departments of Orthopaedics1 and Biomedical Engineering2, Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, NY, USA.

 

Osteoarthritis (OA) is a non-inflammatory degenerative disease of articular cartilage that is projected to afflict >50 million people in the US by 2020.  Not only is the pathogenic basis of OA the subject of ongoing debate, currently the only therapies are palliative:  steroidal or non-steroidal anti-inflammatory agents.  Since the articular chondrocyte is a key player in the maintenance of joint cartilage, and since endochondral ossification-like maturation of this cell is associated with OA in general, factors and signaling pathways that inhibit maturation represent targets for therapy. 

 

Given i) that Parathyroid Hormone (PTH) and PTH-related protein are well documented inhibitors of chondrocyte maturation, and ii) that we have observed upregulation of the PTH receptor type 1 (PTHR1) in chondrocytes residing in injured and degenerating human cartilage, we hypothesize that this factor can inhibit the inappropriate maturation of chondrocytes in OA and prevent/delay the associated degeneration of cartilage matrix. 

 

We employed a widely accepted model of OA in the mouse knee, which involves disruption of the medial collateral ligament and the medial meniscus, to examine the impact of daily administration of Forteo/teriparatide (Eli Lilly formulation of PTH1-34) or PTH(1-34) (teriparatide, Sigma) on the progression of OA following injury.    First, we established that PTHR1 is induced in articular cartilage of mice induced to develop OA via injury. 

 

Quantitative PCR analysis of pooled, dissected articular cartilage from sham or injured joints revealed a five-fold up-regulation of PTHR1 in arthritic cartilage.  We next performed meniscal/ligamentous injury or sham surgery on 10-week-old male C57Bl/6 mice and then began daily systemic treatment with saline, Forteo or PTH(1-34) (Sigma).  A second group of mice were injured but not treated until 8 weeks following injury to determine the effect of teriparatide after initiation of the OA-degenerative process. 

 

Mice were sacrificed at 4, 8, or 12 weeks following injury and joints were harvested for μCT and histology.  μCT revealed increased bone volume in joints from Forteo- and PTH-treated mice, consistent with the well-established anabolic effect of systemic intermittent teriparatide on bone.  In addition, after 12 weeks of Forteo- or PTH treatment, there was 20-27% more articular cartilage compared to saline-treated mice, as determined by quantitative histomorphometry. Strikingly, delayed teriparatide treatment was at least equally if not more effective in protecting against articular cartilage degeneration, with 31-35% more cartilage in Forteo- and PTH-treated groups.  These pre-clinical findings provide strong proof-of-concept support for the potential use of teriparatide to decelerate articular cartilage degeneration in OA patients and delay the onset of morbidities associated with end-stage disease. 
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