Death effects of reveromycin A in chondrocytes and synoviocytes (663.14)

Abstract

Osteoporosis is a prevalent disease with several current treatments. However, these treatments can have harmful long‐term side effects on individuals utilizing them. Reveromycin A (Rev A) is a natural compound that specifically causes apoptosis in osteoclasts but not osteoblasts. To further test whether Rev A can be a safe osteoporosis treatment without detrimental effects in the surrounding joint, the compound’s ability to induce apoptosis and necrosis in ATDC5 murine chondrocytes and HIG‐82 rabbit synoviocytes was measured. Inflammatory joint disease is known to accompany osteoporosis; consequently, Rev A‐induced cell death was characterized in each of these two cell lines under both physiological pH and a pH of 6.8 to mimic the pH of an inflamed joint. After treatment, morphology was assessed through phase contrast microscopy, apoptosis was measured through colorimetric caspase 3 activity assay, and necrosis was quantitated by use of a lactate dehydrogenase (LDH) release assay. Six hours of ten micromolar Rev A treatment did not significantly induce chondrocyte apoptosis, chondrocyte necrosis, or synoviocyte necrosis at either pH. Synoviocyte apoptosis was not induced by Rev A at physiological pH, but at a pH of 6.8, Rev A induced apoptosis compared to untreated by 4.9–fold (p<0.005). The results suggest that Rev A may have undesirable apoptotic effects in synoviocytes of the joint under acidic conditions. Grant Funding Source: Supported by grants from the Indiana Academy of Science and the Hodson Summer Research Institute