title: Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis.
abstract: 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.
authors.affiliation: Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, NY 14642, USA. erik_sampson@urmc.rochester.edu
authors.forename: Erik R
authors.initials: ER
authors.lastname: Sampson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hilton
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mooney
authors.forename: Susan V
authors.initials: SV
authors.lastname: Bukata
authors.forename: Regis J
authors.initials: RJ
authors.lastname: O'Keefe
authors.forename: Hani
authors.initials: H
authors.lastname: Awad
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
authors.forename: Randy N
authors.initials: RN
authors.lastname: Rosier
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zuscik
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000187:drug effects* / Q000473:pathology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008592:Menisci, Tibial / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D054850:Osteophyte / Q000150:complications / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D044968:Regenerative Medicine; D000072099:Serrate-Jagged Proteins; D019379:Teriparatide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000070600:Tibial Meniscus Injuries
chemical_list: D045930:Anabolic Agents; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011509:Proteoglycans; D044168:Receptor, Parathyroid Hormone, Type 1; D000072099:Serrate-Jagged Proteins; D019379:Teriparatide; D053509:Matrix Metalloproteinase 13