Date: Monday, October 22, 2018
Session Title: Osteoarthritis and Joint Biology – Basic Science Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
The most common cause of total joint replacement revision surgeries is loosening of the implant due to loss of bone around the prosthesis. Wear particles shed from the prosthesis plays a critical role by increasing local inflammation and osteoclast number and activity, ultimately causing osteolysis. We have previously reported that an A2A adenosine receptor selective agonist (CGS21680, CGS) prevents osteolysis in wear particle-induced osteolysis model in mice. Frequent administration requirements and potential toxicity make it a less than optimal treatment for inflammatory osteolysis. We therefore generated and tested a novel alendronate-CGS conjugate (MRS7216) that specifically localizes to bone targeting the agonist to the site of tissue injury and thereby diminishing the frequency of administration and curtailing systemic side effects.
The conjugate was synthesized from CGS by sequential activation of the carboxylic acid moiety and reacting with the appropriate amino acid under basic conditions. A PEG6 linker was incorporated to alendronic acid by direct coupling. Osteolysis in 6–8-week-old C57BL/6J mice was induced by surgical implantation of 3mg of ultrahigh-molecular-weight-polyethylene particles over the calvaria. Mice received a weekly 10mg/kg intraperitoneal dose of MRS7216 conjugate, starting at the time of surgery. Other groups of mice were treated with equivalent weekly doses of alendronate-PEG6 (AlenP) or saline respectively. An additional control group underwent sham surgery. After 2 weeks, animals were sacrificed and microCT and histology analyses were performed. The studies were approved by the Institutional Animal Care and Use Committee of NYU School of Medicine.
Receptor binding studies demonstrate that the Ki for CGS, 7216 conjugates and the control AlenP molecules were 21.5 nM, 69.2 nM and >10,000 nM respectively, indicating that MRS7216 efficiently binds the A2A adenosine receptor. MicroCT studies showed that mice treated with weekly doses of 7216 had a significant reduction in bone damage of 40% (p=0.04) compared to saline treated mice. In contrast, AlenP molecules did not prevent bone erosion. Histological analysis of TRAP stained samples showed a significant decrease of osteoclast number/high-power field (HPF) of 55% (p=0.03) in AlenP treated mice compared to the saline treated group. The osteoclast depletion was more dramatic in MRS7216 treated group with an 81% reduction of osteoclasts number/HPF (p= 0.002). Additionally alkaline phosphatase staining in MRS7216 treated group, showed a significant increase in osteoblast number/HPF compared to saline (55%, p=0.01) and to AlenP group (45%, p=0.03).
Alendronate-CGS conjugates represent a novel therapeutic approach to prevent osteolysis and prosthetic failure in patients with prosthetic joints.
To cite this abstract in AMA style:Larrañaga Vera A, Toti K, Warnick E, Rao H, Gao ZG, Gadiano A, Mediero A, Jacobson KA, Cronstein BN. Alendronate-CGS21680 Conjugates Prevent Bone Erosion in a Murine Osteolysis Model [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/alendronate-cgs21680-conjugates-prevent-bone-erosion-in-a-murine-osteolysis-model/. Accessed June 6, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alendronate-cgs21680-conjugates-prevent-bone-erosion-in-a-murine-osteolysis-model/