Osteoporosis has become a high incident bone disease along with the aging of human population. Long noncoding RNAs (LncRNAs) play an important role in osteoporosis incidence. In this study, we screened out an LncRNA negatively correlated with osteoblast differentiation, which was therefore named Lnc-DIF (differentiation inhibiting factor). Functional analysis proved that Lnc-DIF inhibited bone formation. A special structure containing multiple 53 nucleotide repeats was found in the trailing end of Lnc-DIF. Our study suggested that this repeat sequence could sequester multiple miR-489-3p and inhibit bone formation through miR-489-3p/SMAD2 axis. Moreover, siRNA of Lnc-DIF would rescue bone formation in both aging and ovariectomized osteoporosis mice. This study revealed a kind of LncRNA that could function as a sponge and regulate multiple miRNAs. RNA therapy techniques that target these LncRNAs could manipulate its downstream miRNA-target pathway with significantly higher efficiency and specificity. This provided potential therapeutic insight for RNA-based therapy for osteoporosis.

Osteoporosis poses a significant threat to human health. Long non-coding RNAs (LncRNAs) have been deemed as crucial regulators in the pathogenesis of osteoporosis. However, the accuracy and efficiency of LncRNA-mediated regulation of bone formation require further improvement. Our previous study identified a repeat sequence in the human-derived LncRNA CTD-2555A7.2, suggesting its potential role in osteoporosis regulation. To investigate this hypothesis, we conducted systematic functional analyses of CTD-2555A7.2 in osteogenesis and explored its mechanisms and potential therapeutic applications. Through over-expression, siRNA silencing and repeat sequence over-expression in vitro and in vivo, our research demonstrate that CTD-2555A7.2 enhances bone formation by sequestering multiple miR-381-3p molecules through its repeat sequence. Through Western blot, siRNA silencing and luciferase reporter assay, we illuminated miR-381-3p suppresses osteogenic differentiation by concurrently targeting four essential genes of the Wnt signaling pathway: Apc, Lef1, wnt5a, and Lrp6. Notably, the mRNA of CTD-2555A7.2 repeat sequence exhibited pronounced therapeutic efficacy in ovariectomy osteoporosis models. Taken together, we identified a dual-amplification osteogenic axis (CTD-2555A7.2-miR-381-Wnt) that demonstrates significant regulatory effects on osteoporosis. This study has established an important theoretical framework for understanding osteogenic LncRNA mechanisms and provides novel insights for developing targeted therapeutics against osteoporosis.

Long non-coding RNAs (LncRNAs) play essential roles in multiple physiological processes including bone formation. Investigators have revealed that LncRNAs regulated bone formation through various signaling pathways and micro RNAs (miRNAs). However, several problems exist in current research studies on osteogenic LncRNAs, including sophisticated techniques, high cost for in vivo experiment, as well as low homology of LncRNAs between animal model and human, which hindered translational medicine research. Moreover, compared with gene editing, LncRNAs would only lead to inhibition of target genes rather than completely knocking them out. As the studies on osteogenic LncRNA gradually proceed, some of these problems have turned osteogenic LncRNA research studies into slump. This review described some new techniques and innovative ideas to address these problems. Although investigations on osteogenic LncRNAs still have obtacles to overcome, LncRNA will work as a promising therapeutic drug for osteoporosis in the near future.

Editorial: Post-transcriptional regulation and its misregulation: From molecular basis to translational medicine

Background: Osteoporosis is classically defined by reduced bone mass and microarchitectural deterioration, but osteoimmune dysregulation within the bone marrow microenvironment is increasingly recognized as an important contributor to bone loss. The RANKL/RANK/OPG axis represents a dominant pathway governing osteoclast differentiation and bone resorption, yet its activity is shaped by macrophage activation, T-cell subset imbalance, and cytokine feedback loops. Existing reviews often examine these components separately; fewer conceptualize their network-level convergence on RANKL-dependent osteoclastogenesis across osteoporosis subtypes and disease stages. Methods: Literature was searched in PubMed, Web of Science, and Scopus using combinations of “osteoporosis”, “osteoimmunology”, “RANKL”, “macrophage polarization”, “Th17”, “Treg”, “cytokine”, and related terms. Priority was given to mechanistic studies, animal models, clinical observational studies, and recent reviews directly relevant to RANKL-dependent osteoclastogenesis and bone marrow immune regulation. Results: Pro-inflammatory M1-like macrophages, Th1/Th17 responses, and cytokines such as TNF-α, IL-1β, IL-6, and IL-17 may promote osteoclastogenesis by upregulating RANKL expression, increasing the RANKL/OPG ratio, and enhancing the responsiveness of osteoclast precursors to RANKL. Together, these mechanisms form a pro-inflammatory and pro-osteoclastogenic amplification loop. Conversely, M2-like macrophages, osteal macrophages, Treg/Th2 responses, and factors such as IL-10, TGF-β, IL-4, IL-13, and OPG may restrain excessive osteoclast formation and contribute to inflammation resolution, immune tolerance, and bone repair. Different forms of osteoporosis may share RANKL-dependent bone resorption as a common final effector process, yet differ substantially in their upstream immune drivers. Conclusion: Interpreting RANKL as a convergent effector node, rather than a RANKL-exclusive explanation, provides a framework for understanding osteoporosis heterogeneity and guiding osteoimmune-based stratification. Future studies incorporating human bone marrow samples, longitudinal cohorts, single-cell and spatial omics, immunometabolic analyses, and bone-targeted delivery technologies are needed to validate network states and translate immunomodulatory strategies into individualized osteoporosis management.