Effects of thionapthene 2-carboxylic acid and related compounds on bone resorption in organ culture

Summary We have compared the effects of thiophene 2-carboxylic acid (TCA) and a number of sulfur-and nitrogen-containing analogs for their ability to inhibit bone resorption in organ cultures of fetal rat long bones. Four compounds,—thionapthene-2-carboxylic acid (TNCA), dibenzo-thiophene-4-carboxylic acid, indole-2-carboxylic acid and carbazole-1-carboxylic acid—caused a doserelated inhibition of PTH-stimulated bone resorption, although TCA was ineffective in this system. TNCA at 3×10⁻⁴ M or 10⁻⁴ M was the most potent inhibitor of PTH-stimulated bone resorption and was selected for further study. TNCA also inhibited stimulation of resorption by prostaglandin E₂ and 1,25-dihydroxyvitamin D. Unlike calcitonin, the effect of TNCA was persistent and did not show escape. Moreover, TNCA could inhibit resorption in bones that had previously escaped from calcitonin. TNCA did not appear to be a nonspecific toxin, since it did not decrease incorporation of [³H] thymidine or [³H]proline into fetal rat long bones. The fact that resorption in unstimulated cultures was only decreased when the control rates were high also argues against nonspecific toxicity. Moreover, this suggests that TNCA will be most effective under conditions of accelerated bone resorption when an inhibiting effect is most desirable. heterocyclic sulfur-containing compound, thiophene-2 carboxylic acid (TCA) in the rat. Subsequent studies showed that this compound could inhibit bone resorption in organ cultures of neonatal mouse calvaria [3]. We have compared TCA with a number of analogs for their ability to inhibit PTH stimulated bone resorption in organ culture. TCA itself was found to be relatively ineffective, whereas several of the analogs were inhibitory at concentrations of 3×10⁻⁴ or 10⁻⁵ M. One of the most potent compounds, thionapthene 2-carboxylic acid (TNCA) was selected for further study. TNCA was a potent inhibitor not only of PTH stimulated bone resorption, but of resorption stimulated by prostaglandin E₂ (PGE₂) and 1,25-dihydroxyvitamin D (1,25-(OH)₂D₃). It was less effective in inhibiting resorption in control unstimulated cultures. TNCA did not appear to act as a nonspecific toxin in that it did not decrease [³H]-thymidine or [³H]-proline incorporation into bones. The inhibitory effect of TCA was persistent, unlike that of calcitonin, which shows escape after initial inhibition. Moreover, TNCA had a powerful inhibitory effect when it was added to bones that had previously escaped from CT. A preliminary report of this work was presented at the sixth annual meeting of the American Society for Bone and Mineral Research, Hartford, CT. 1984 [1]