Pharmacokinetic/pharmacodynamic (PK/PD) differentiation of native and PEGylated recombinant human growth hormone (rhGH and PEG-rhGH) in the rat model of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease that has no FDA-approved treatment. The current standard of care does not address the regeneration of the damaged cartilage. Human growth hormone (hGH) is part of the insulin-like growth factor (IGF)-1 axis. There has been preclinical data that suggest its potential regenerative property in the joint. However, unformulated recombinant hGH (rhGH) is short-lived in the joint, and does not provide a desirable pharmacokinetic (PK) profile to support a clinical treatment paradigm. Polyethylene glycol (PEG)ylation is a potential method to extend the half-life of rhGH in the joint. The purpose of this study was to delineate the PK/PD profile of PEG-rhGH in the knee joint in a rat preclinical model of OA. After intra-articular (IA) injection of 100 microg into a rat knee joint that underwent medial meniscectomy, PEG-rhGH exhibits 2-fold longer half-lives in joint than native hGH. However, PEG-rhGH has a much longer systemic exposure. IA injections of PEG-rhGH also resulted in higher levels of IGF-1 in the joint and serum when compared with native rhGH. In order to develop PEG-rhGH as an IA therapeutic treatment for OA, careful dose selection is necessary to avoid systemic effects while retaining its anabolic efficacy in the joint.

Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction.

Mitogen-activated protein kinase (MAPK) pathways are implicated in joint destruction in rheumatoid arthritis (RA) by modulating the production and functions of inflammatory cytokines. Although p38 MAPK (p38) participates in signaling cascades leading to osteolysis in arthritis, the mechanisms of its action in this process remain incompletely understood. Here, we found that the osteoclast (Ocl) precursors expressed p38alpha, but not p38beta, p38delta, and p38gamma isoforms. Treatment of these cells with receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) resulted in p38 activation. Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-alpha was blocked with the novel p38 inhibitor 4-(3-(4-chlorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (SC-409). To validate in vitro data, p38 role was further investigated in streptococcal cell wall (SCW)-induced arthritis in rats. We found that SCW-induced joint swelling and bone destruction were attenuated by SC-409. Mechanistically, the data show that SCW-stimulated DNA binding activity of the transcription factor myocyte-enhancing factor 2 C, which is downstream of p38, was inhibited by SC-409. In addition, SC-409 inhibited SCW-stimulated expression of numerous factors, including TNF-alpha, interleukin-1beta, and RANKL. Although c-Jun NH2-terminal kinase and NF-kappaB pathways were activated in vitro by RANKL and in vivo by SCW, SC-409 had no significant effect on these pathways. In conclusion, our data show that p38 modulates the production and signaling of cytokines, thus providing a mechanism of the bone-sparing effect of SC-409 in rat arthritis. These data present SC-409 as a novel potent p38 inhibitor and suggest that p38-based therapies may be beneficial in preventing bone loss associated with RA.