Combination gene therapy targeting on interleukin-1β and RANKL for wear debris-induced aseptic loosening

Abstract

This study investigated the efficacy of a combination gene therapy to repress IL-1 and RANKL for the treatment of particulate debris-induced aseptic loosening, and tried to explore the molecular mechanism the exogenous gene modifications on osteoclastogenesis. RAW cells activated by titanium particles were transduced with DFG-IL-1Ra and AAV-OPG individually or in combination for 4 weeks. Pro-inflammatory cytokines in culture media were determined by ELISA, and gene expressions of RANK, IL-1β, c-Fos, TRAF6, JNK1, and CPK were examined using real-time PCR. An established knee-implant-failure mouse model was employed to evaluate the efficacy of the in vivo double-gene therapy. The surgical implantation of a titanium alloy pin into the proximal tibia was followed by monthly challenge with titanium debris. Peri-implant gene transfers of IL-1Ra and OPG (respectively or in combination) were given three weeks after surgery. The combination of OPG and IL-1Ra gene transfer exhibited strong synergetic effects in blockage of inflammation and osteoclastogenesis at 8-weeks after gene modification. The combination therapy reversed peri-implant bone resorption and restored implant stability when compared with either single gene transduction. Real-time PCR data indicated that the action of IL-1Ra gene therapy may be mediated via the JNK1 pathway, while the reduction of osteoclastogenesis by OPG gene modification may be regulated by c-Fos expression. In addition, both gene modifications resulted in significantly diminishment of TRAF6 expression.

Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement

“…Systemic treatments attempting to limit one pro-inflammatory cytokine or induce osteoclast apoptosis have been unsuccessful in mitigating osteolysis. In vitro and in vivo models that use some novel therapies to modulate particle-induced inflammation, for example gene therapy, risk potential adverse events [26].…”

The fibroblast expression of RANKL in CoCrMo-particle-induced osteolysis is mediated by ER stress and XBP1s

“…However, periprosthetic osteolysis and subsequent aseptic loosening (AL) remain the most common reasons for total hip arthroplasty (THA) failure and revision http surgery [2,3]. Various wear particles, liberated from the surface of prostheses, play a critical role in aseptic loosening [4,5]. Particles induce a chronic inflammatory response, which manifests as a granulomatous membrane consisting predominantly of fibroblasts, macrophages, and foreign body giant cells, resulting in resorption of bone [6].…”

Adenoviral vector-mediated overexpression of osteoprotegerin accelerates osteointegration of titanium implants in ovariectomized rats

“…[15][16][17] Recombinant OPG was also a potent pharmacologic inhibitor of bone resorption. 18,19 Thus, hOPG might be an effective candidate to inhibit the bone remodeling.…”