Teriparatide as a Chondroregenerative Therapy for Injury-Induced Osteoarthritis

Teriparatide is chondroprotective and chondroregenerative in a mouse model of injury-induced osteoarthritis of the knee. Extending the Service Life of Arthritic Joints Every year, millions of people with osteoarthritis are forced to scale back their physical activities hoping to alleviate pain and increase the longevity of their degenerating joints. The problem is serious: A decade from now, 25% or more of the U.S. population are predicted to suffer from osteoarthritis. The hallmark problem in osteoarthritis is the progressive and irreversible loss of cartilage. Ultimately, the only option is to surgically replace the lost cartilage with metal and plastic. But are there alternative strategies that could lead to cartilage replacement and reduce the cycle of pain and reduced quality of life? In this issue of Science Translational Medicine, Sampson and colleagues report that a naturally occurring hormone called parathyroid hormone (trade name Forteo), already approved by the Food and Drug Administration to build bone, can also boost the buildup of cartilage in a mouse model of injury-induced osteoarthritis. In this mouse model, injury to the meniscus and ligaments of the knee initiates a slow process of cartilage degeneration that is comparable to that seen in people suffering a similar injury. To approximate the clinical situation of treating someone with symptomatic osteoarthritis caused by a past trauma, the researchers administered parathyroid hormone to mice that were already osteoarthritic because of an injury to the medial meniscus and medial collateral ligament. Tissue and molecular analyses of the injured knee joints revealed that after 1 month of daily treatment with parathyroid hormone, the cartilage layer was 32% thicker than in injured mice that did not receive the hormone. In addition, the investigators noted an increase in production of matrix molecules by chondrocytes (the cells that produce cartilage), suppression of genes associated with inappropriate chondrocyte maturation, and a reduction in cartilage breakdown. The ability of parathyroid hormone to boost the addition of new cartilage matrix while blocking its degradation in osteoarthritic joints suggests that it may be a useful therapeutic for treating patients with osteoarthritis, a pervasive clinical condition with surgery as the only current solution. There is no disease-modifying therapy for osteoarthritis, a degenerative joint disease that is projected to afflict more than 67 million individuals in the United States alone by 2030. Because disease pathogenesis is associated with inappropriate articular chondrocyte maturation resembling that seen during normal endochondral ossification, pathways that govern the maturation of articular chondrocytes are candidate therapeutic targets. It is well established that parathyroid hormone (PTH) acting via the type 1 PTH receptor induces matrix synthesis and suppresses maturation of chondrocytes. We report that the PTH receptor is up-regulated in articular chondrocytes after meniscal injury and in osteoarthritis in humans and in a mouse model of injury-induced knee osteoarthritis. To test whether recombinant human PTH(1–34) (teriparatide) would inhibit aberrant chondrocyte maturation and associated articular cartilage degeneration, we administered systemic teriparatide (Forteo), a Food and Drug Administration–approved treatment for osteoporosis, either immediately after or 8 weeks after meniscal/ligamentous injury in mice. Knee joints were harvested at 4, 8, or 12 weeks after injury to examine the effects of teriparatide on cartilage degeneration and articular chondrocyte maturation. Microcomputed tomography revealed increased bone volume within joints from teriparatide-treated mice compared to saline-treated control animals. Immediate systemic administration of teriparatide increased proteoglycan content and inhibited articular cartilage degeneration, whereas delayed treatment beginning 8 weeks after injury induced a regenerative effect. The chondroprotective and chondroregenerative effects of teriparatide correlated with decreased expression of type X collagen, RUNX2 (runt-related transcription factor 2), matrix metalloproteinase 13, and the carboxyl-terminal aggrecan cleavage product NITEGE. These preclinical findings provide proof of concept that Forteo may be useful for decelerating cartilage degeneration and inducing matrix regeneration in patients with osteoarthritis.