PMSA as a potential modulator of calcineurin phosphatase activity.

Osteoporosis is a major skeletal disorder characterized by reduced bone strength and increased risk of fractures. Excessive osteoclast-mediated bone resorption is a primary cause of this condition, underscoring the need for effective anti-resorptive therapies. N-phenyl-methylsulfonamido-acetamide (PMSA) compounds have been previously identified as potential anti-resorptive agents that inhibit osteoclastogenesis. In this study, ribonucleic acid (RNA)-sequencing and proteomic analyses identified calcineurin (CaN) as a potential target of PMSA implicated in osteoclast differentiation. PMSA bound to CaN and suppressed its phosphatase activity, which is essential for the activation and translocation of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a key regulator of osteoclastogenesis. PMSA treatment resulted in altered NFATc1-related signaling and increased phospho-NFATc1 levels in osteoclasts. Overall, these findings suggest that PMSA may inhibit CaN activity during osteoclast differentiation, positioning it as a promising therapeutic candidate for osteoporosis.