The discovery of novel molecular targets to enhance the osteogenesis of human bone marrow-derived mesenchymal stem cells (H-BMSCs) represents a promising strategy for preventing and treating osteoporosis. Thus, the primary objective of this study is to elucidate the mechanisms by which long non-coding RNA FOXD2-AS1 (lncRNA FOXD2-AS1) regulates early osteogenic differentiation in H-BMSCs, thereby identifying potential therapeutic targets.

Lentivirus-mediated vectors were constructed to either overexpress or silence FOXD2-AS1 in H-BMSCs. The effects of FOXD2-AS1 on osteogenesis were subsequently assessed by analyzing osteogenic marker expression and alkaline phosphatase (ALP) staining. To clarify the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3) pathway in this process, AG490 inhibitor (a JAK2/STAT3 pathway inhibitor) and knockdown of STAT3 were used to investigate the mechanisms of FOXD2-AS1.

FOXD2-AS1 overexpression increased ALP activity and osteogenic marker expression, while its knockdown had the opposite effects. From a mechanistic perspective, FOXD2-AS1 overexpression promoted JAK2 and STAT3 phosphorylation, whereas its suppression attenuated their activation. Also, the osteogenic increase induced by FOXD2-AS1 overexpression was reversed by AG490 treatment or STAT3 silencing, indicating that the pathway plays a role in this process.

FOXD2-AS1 was identified as a novel genetic switch driving osteogenic commitment via JAK2/STAT3 activation, revealing a new regulatory mechanism and a potential therapeutic target for osteoporosis.