Objectives Osteoarthritis (OA) is a degenerative joint disease and easily to decrease glycosaminoglycan (GAG) and collagen levels, but the mechanism remains unclear. During OA progression, articular chondrocytes undergo terminal differentiation, and decrease level of GAG and COL. II, but increase level of COL. X, that similar as those during endochondral ossification. Previous studies showed that parathyroid hormone-related peptide (PTHrP) can suppress hypertrophy and terminal differentiation of chondrocytes. Previous studies also indicated that PTHrP and parathyroid hormone (PTH) share the same receptor, PTHR1, and stimulate activities of adenylate cyclase (PKA pathway) and phospholipase-C (PKC pathway). Our previous finding emphasized that PTH(1-34) can suppress the progress of terminal differentiation in cultured human articular chondrocytes (HACs) and the papain-induced OA in rats. The results showed that intra-articular injection of PTH(1-34) once every 3days suppressed chondrocyte terminal differentiation in osteoarthritis(OA) cartilage and in turn suppressed the progression of OA; however, the treatment strategy is with too frequent injection. To develop an effective carrier for PTH(1-34), which can controlled-release for prolonging duration is critical. We hypothesized that the controlled-release of PTH(1-34) from PLGA encapsulation can suppress progression of OA in early stage. The objective of this work is to develop the PTH(1-34) encapsulated PLGA microspheres and study the effect of controlled-released PTH(1-34) from PLGA microspheres on suppression of the OA progression. Methods The PTH(1-34) encapsulated PLGA microspheres were prepared by a double emulsion method (W/O/W). The surface morphology and size of the microspheres were evaluated by the scanning electron microscope (SEM) and particle size analysis, respectively. To mimic the physiological condition the release of PTH(1-34) from PLGA microspheres were incubated in normal saline (0.9% NaCl), and the concentration of PTH(1-34) in the effluent is determined by ELISA. The released PTH(1-34) was biologically active as evidenced by the stimulated release of cAMP from MC3T3-E1 osteoblast-like cell. In the in vivo study, we studied the effect of different doses of PTH(1-34)(5X10-9M – 10-7M) and PTH/PLGA(0.4mg) on articular cartilage of knee joint of rats in papain-induced OA and non-OA group. The histologic changes in GAG, type II collagen, and type X collage were evaluated with safranin-o stain and immunohistochemistry (IHC) stain, respectively. Results The size of the microspheres was 51.93um~75.94μm. The SEM observation emphasized that the microsphere were constantly decomposed follows the time. The PLGA microspheres can efficiently encapsulated 72% of PTH(1-34), and the PTH released from microspheres was detectable through 3 weeks at consistent rate. The bioactivity data showed that the released PTH(1-34) from microspheres at the 1st and 3rd day increased the cAMP level in MC3T3-E1 cells, indicating the released PTH(1-34) was still bioactive. In the in vivo result, in non-OA cartilages, there were no significant differences on GAG, COL. II and COL. X expressions among the control and drug treatment groups [PTH(1-34)(5X10-9M – 10-7M) and PTH/PLGA(0.4mg)]. In the papain induced OA cartilages, different doses of PTH(1-34)(5x10-9M – 10-7M) and PTH/PLGA(0.4mg) treatments were both capable to reverse papain-induced OA changes by increasing GAG and type II collagen levels and decreasing type X collagen level in the knee cartilage of rats, and which had no difference comparing to the control group. Conclusion The result in this study showed that the feasibility of achieving controlled local delivery of PTH(1-34) and maintain their constant concentration by PLGA encapsulation method. The animal study indicated that the different treatment doses of PTH(1–34)(5X10-9M - 10-7M) and PTH/PLGA(0.4mg) were both capable to inhibit the progression of OA in rats, and had no adverse effect on the cartilage in non-OA group. According to the results, we suggest that intra-articular injection of PTH/PLGA microspheres may be used to treat OA.