OBJECTIVE: Emerging evidence suggests long noncoding RNA H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biologic function of H19 in OA subchondral bone remodeling and OA progression. METHODS: Clinical joint samples and OA animal models induced by surgical destabilization of the medial meniscus (DMM) were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechanoresponse. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment. RESULTS: Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass, with more H19 mice expressing osteocytes. On the contrary, mice with osteocyte-specific deletion of H19 are less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechanoresponse through PI3K/AKT/GSK3 signal activation by EZH2-induced H3K27me3 regulation on protein phosphatase 2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype. CONCLUSION: In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.