title: Sustained release of PTH(1-34) from PLGA microspheres suppresses osteoarthritis progression in rats.
abstract: We previously reported that PTH(1-34) inhibits the terminal differentiation of articular chondrocytes and, in turn, suppresses the progression of osteoarthritis (OA). However, this treatment requires an injection of PTH(1-34) once every 3 days over the treatment period. In this study, we studied the effect of sustained administration of PTH(1-34) in a papain-induced OA rat model. We developed an effective controlled-release system for prolonging the treatment duration of an intra-articular injection for OA treatment in rats. The effects of released PTH(1-34) from PLGA(65:35)-encapsulated PTH(1-34) microspheres (PTH/PLGA) on papain-induced OA in rat knees were studied. Microsphere morphology was observed in vitro by scanning electron microscopy, and microsphere size was determined with a particle size analyzer. The PTH(1-34) encapsulation efficiency and release profile, as well as the toxicity of PTH/PLGA, were examined. The bioactivity of released PTH(1-34) was tested by examining cAMP levels in MC3T3E1 cells. In vivo, we evaluated the changes of localized GAG, Col II, and Col X in the articular cartilage of rat knees. Our results demonstrated that the surface of the PLGA microspheres was smooth, and the size of the microspheres was in the range of 51-127 μm. PTH/PLGA microspheres sustainably released PTH(1-34) for 19 days with a concentration range of 0.01-100 nM that covered the expected concentration of 10nM at 37°C. The cAMP levels of MC3T3E1 cells were elevated in the response to released PTH(1-34) from PTH/PLGA microspheres, indicating that the released PTH(1-34) is bioactive. Most importantly, intra-articular treatment with either PTH(1-34) (0.1-100 nM) 3 days/injection or PTH/PLGA microspheres (15 days/injection) for 5 weeks revealed the similar effect on suppressing papain-induced OA changes (decreasing GAG and Col II and increasing Col X) in rat knee cartilage. The effect of PTH/PLGA microspheres on suppressing OA progression was similar to that of a once-every-three-day injection of PTH(1-34), indicating that both the sustained and intermittent action of PTH(1-34) effectively suppress OA progression. The developed PLGA microspheres with sustained release and long-term effect may be potent carriers for PTH(1-34) used to treat early OA.
authors.affiliation: Orthopedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Rajalakshmanan
authors.initials: R
authors.lastname: Eswaramoorthy
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Shun-Cheng
authors.initials: SC
authors.lastname: Wu
authors.forename: Gwo-Jaw
authors.initials: GJ
authors.lastname: Wang
authors.forename: Je-Ken
authors.initials: JK
authors.lastname: Chang
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Ho
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018450:Disease Progression; D004337:Drug Carriers; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D010003:Osteoarthritis / Q000188:drug therapy* / Q000473:pathology; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004337:Drug Carriers; D010281:Parathyroid Hormone