Age‐Related Decrease in Pellino‐1 Expression Contributes to Osteoclast‐Mediated Bone Loss

Abstract Aging‐related bone loss is driven by various biological factors, such as imbalanced bone metabolism from decreased osteoblast and increased osteoclast activities. Various transcriptional and post‐transcriptional factors increase osteoclast activity with aging; however, studies regarding the post‐translational regulators of osteoclast activity are still limited. The ubiquitin E3 ligase Pellino‐1 is a well‐known post‐translational regulator of inflammation. However, how Pellino‐1 expression regulation affects osteoclast differentiation remains unclear. This study determined that Pellino‐1 levels are reduced in bone marrow monocytes (BMMs) from 40‐week‐old mice compared to 4‐week‐old mice. Interestingly, conditional Knockout (cKO) of Pellino‐1 in 6‐week‐old mice resulted in decreased bone mass, reduced body size, and lower weight than in Pellino‐1 floxed mice; however, these differences are not observed in 20‐week‐old mice. The increased number of tartrate‐resistant acid phosphatase (TRAP)‐positive cells and serum levels of C‐terminal telopeptides of type I collagen, a marker of bone resorption, in 6‐week‐old Pellino‐1 cKO mice implied a connection between Pellino‐1 and the osteoclast population. Enhanced TRAP activity and upregulation of osteoclast genes in BMMs from the cKO mice indicate that Pellino‐1 deletion affects osteoclast differentiation, leading to decreased bone mass and heightened osteoclast activity. Thus, targeting Pellino‐1 could be a potential gene therapy for managing and preventing osteoporosis.