Session Title: Osteoarthritis & Joint Biology – Basic Science Poster
Session Type: Poster Session (Tuesday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Implant loosening due to loss of bone is the most common cause of total joint replacement revision surgeries. One of the main cause of osteolysis is the shed of wear particles from the implant as it causes an increased local inflammation and osteoclast number and activity. It is known that an A2A adenosine receptor selective agonist (CGS21680, CGS) prevents bone loss in wear particle-induced osteolysis model in mice. But frequent administration requirements and its potential to cause side effects make it a less than optimal treatment. 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.
Methods: 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 (WT) or A2A KO 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. New bone formation was studied by Calcein/Alizarin Red‐labeling. 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.
Results: 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 WT mice treated with weekly doses of MRS7216 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. Similarly in A2A KO mice MRS7216 treatment did not prevent bone damage. 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 WT 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 per HPF compared to saline (55%, p=0.01) and to AlenP group (45%, p=0.03). Furthermore Double bone labeling with calcein/alizarin red showed a significant increase on femurs bone formation of MRS7216 treated group compared to saline and to Alendronate group (p=0.0092 and p=0.0345).
Conclusion: Alendronate-CGS conjugates represent a novel and specific therapeutic approach to inhibit osteolysis and stimulate new bone formation to prevent prosthetic failure in patients with prosthetic joints or other bone pathologies.
To cite this abstract in AMA style:Larrañaga-Vera A, Toti K, Sussman S, Warnick E, Rao H, Gao Z, Gadiano A, Mediero A, Jacobson K, Cronstein B. Alendronate-CGS21680 Conjugates Prevent Bone Erosion in a Murine Osteolysis Model but Not in A2A KO Mice [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/alendronate-cgs21680-conjugates-prevent-bone-erosion-in-a-murine-osteolysis-model-but-not-in-a2a-ko-mice/. Accessed November 30, 2020.
« Back to 2019 ACR/ARP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/alendronate-cgs21680-conjugates-prevent-bone-erosion-in-a-murine-osteolysis-model-but-not-in-a2a-ko-mice/