Polydeoxyribonucleotide Promotes Longitudinal Bone Growth Through the Hepatic JAK2-STAT5/IGF-1 Axis Involving A2A Receptor Signaling

Longitudinal bone growth is primarily regulated by the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis. However, non-hormonal and orally administered strategies for promoting longitudinal growth remain limited. Here, we investigated the effects and mechanisms of polydeoxyribonucleotide (PDRN) on longitudinal bone growth in vitro and in vivo. In HepG2 cells, PDRN significantly increased IGF-1 mRNA expression and JAK2 and STAT5 phosphorylation without affecting cell viability. Pretreatment with ZM241385, a selective adenosine A2A receptor (A2AR) antagonist, significantly attenuated these responses, supporting the involvement of A2AR signaling. In mice, oral PDRN for 5 weeks significantly increased body length gain, growth plate thickness, and hepatic JAK2/STAT5 activation, elevating serum IGF-1 levels without altering GH levels or systemic toxicity markers. Quantitative micro-computed tomography analysis demonstrated improved trabecular and cortical bone microarchitecture with reduced porosity. Furthermore, PDRN modulated bone remodeling-related responses by suppressing lipopolysaccharide-induced osteoclastogenic marker expression in RAW 264.7 cells and enhancing osteogenic marker expression while downregulating RANKL in MC3T3-E1 cells. Overall, oral PDRN promotes longitudinal bone growth and improves microarchitecture via increased hepatic IGF-1 signaling and altered bone remodeling-related gene expression, supporting its potential as an oral candidate for skeletal growth.