人类基因组中的长非编码 RNA (lncR) ANRIL 是动脉粥样硬化、牙周炎、糖尿病和癌症的既定遗传风险因素。然而，lncR-ANRIL 在骨和脂肪组织代谢中的调节作用仍不清楚。为了阐明lncRNA ANRIL在小鼠模型中的功能，我们研究了其直系同源物AK148321（称为lncR-APDC），其位于小鼠基因组的chr4上，假设其与ANRIL具有相似的生物学功能。我们最初发现小鼠骨髓细胞（BMSC）中的lncR-APDC和人成骨细胞（hFOB）中的lncR-ANRIL在早期成骨过程中均增加。随后，我们用lncR-APDC缺失/过表达细胞模型检查了成骨、脂肪生成、破骨细胞生成功能。在体内，我们比较了 APDC-KO 和野生型小鼠之间骨和脂肪组织的表型差异。我们的研究结果表明，lncR-APDC 缺陷会损害成骨作用，同时促进脂肪生成和破骨细胞生成。相反，lncR-APDC 的过度表达刺激成骨，但损害脂肪生成和破骨细胞生成。此外，KDM6B 在 lncR-APDC 缺乏时下调，在过表达时上调。通过结合位点分析，我们确定 miR-99a 是 lncR-APDC 的潜在靶标。结果表明lncR-APDC通过miR-99a/KDM6B/Hox途径发挥其成骨功能。此外，lncR-APDC 通过 MAPK/p38 和 TLR4/MyD88 激活介导破骨细胞-成骨失衡。这些发现强调了 lncR-APDC 作为骨和脂肪组织代谢关键调节剂的关键作用。它显示了解决成骨、脂肪生成和破骨细胞生成失衡的潜在治疗方法。

The long noncoding RNA (lncR) ANRIL in the human genome is an established genetic risk factor for atherosclerosis, periodontitis, diabetes, and cancer. However, the regulatory role of lncR-ANRIL in bone and adipose tissue metabolism remains unclear. To elucidate the function of lncRNA ANRIL in a mouse model, we investigated its ortholog, AK148321 (referred to as lncR-APDC), located on chr4 of the mouse genome, which is hypothesized to have similar biological functions to ANRIL. We initially revealed that lncR-APDC in mouse bone marrow cells (BMSCs) and lncR-ANRIL in human osteoblasts (hFOBs) are both increased during early osteogenesis. Subsequently, we examined the osteogenesis, adipogenesis, osteoclastogenesis function with lncR-APDC deletion/overexpression cell models. In vivo, we compared the phenotypic differences in bone and adipose tissue between APDC-KO and wild-type mice. Our findings demonstrated that lncR-APDC deficiency impaired osteogenesis while promoting adipogenesis and osteoclastogenesis. Conversely, the overexpression of lncR-APDC stimulated osteogenesis, but impaired adipogenesis and osteoclastogenesis. Furthermore, KDM6B was downregulated with lncR-APDC deficiency and upregulated with overexpression. Through binding-site analysis, we identified miR-99a as a potential target of lncR-APDC. The results suggest that lncR-APDC exerts its osteogenic function via miR-99a/KDM6B/Hox pathways. Additionally, osteoclasto-osteogenic imbalance was mediated by lncR-APDC through MAPK/p38 and TLR4/MyD88 activation. These findings highlight the pivotal role of lncR-APDC as a key regulator in bone and fat tissue metabolism. It shows potential therapeutic for addressing imbalances in osteogenesis, adipogenesis, and osteoclastogenesis.