Cascades From Caspase‐Dependent Osteoblast Death to Purinergic Signaling in the Pathogenesis of Osteoporosis: Novel Roles of Caspases in Bone Remodeling

ABSTRACT

Dying cells actively secrete ATP as a ‘find‐me’ signal, which is detected by P2 purinergic receptors on macrophages and activates intracellular purinergic signaling to initiate apoptotic cell clearance. Hyperactivation of purinergic signaling due to excessive extracellular ATP (eATP) is associated with various pathological states. Osteoporosis is a systemic metabolic bone disorder characterized by decreased osteoblasts and increased osteoclasts. Notably, osteoblasts have been identified as the primary source of eATP in the bone microenvironment. Sustained osteoblast death under osteoporotic conditions may lead to excessive eATP release, which further exacerbates bone remodeling disruption potentially via purinergic signaling hyperactivation in the bone microenvironment. However, the roles of purinergic signaling in the pathogenesis of osteoporosis have not been systematically summarized. Therefore, we provide an overview of the release of eATP from dying cells and its subsequent activation of macrophages via P2 purinergic receptors in this review. Furthermore, we propose a novel hypothesis for osteoporosis that sustained caspase‐dependent osteoblast death triggers excessive ATP secretion, which could further inhibit osteoblast activities and promote osteoclast activities. Several anti‐purinergic agents have exhibited therapeutic potential for osteoporosis; however, further studies are required to clarify the specific mechanisms through which purinergic signaling contributes to osteoporosis.