i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal.
Cell Death Dis. 2024 Oct 11;15(10):741. doi: 10.1038/s41419-024-06983-1.
Osteoclasts are the only cells able to resorb all the constituents of the bone matrix. While the modulation of osteoclast activity is well established for preventing bone-related diseases, there is an increasing demand for novel classes of anti-resorption agents. Herein, we investigated non-coding RNA molecules and proposed DLEU1 and miR-16 as potential candidates for modulating osteoclast functions. DLEU1 and miR-16 target cell fusion at both the early and late stages of osteoclastogenesis but operate through independent pathways. DLEU1 silencing hinders the fusion process, leading to abrogation of the phagocytic cup fusion modality and a reduction in the fusion events between mononucleated precursors and multinucleated osteoclasts, while miR-16 influences monocyte-to-osteoclast differentiation, impairing osteoclasts formation but not the number of nuclei at early stages. On the other hand, using these non-coding RNAs to engineer mature osteoclasts has implications for bone resorption. Both DLEU1 and miR-16 influence the speed of resorption in pit-forming osteoclasts, without affecting the resorbed area. However, the impact of increasing miR-16 levels extends more broadly, affecting trench-forming osteoclasts as well, leading to a reduction in their percentage, speed, and resorbed area. These findings offer potential new therapeutic targets to ameliorate bone destruction in skeletal diseases.
破骨细胞是唯一能够吸收骨基质所有成分的细胞。虽然已经明确了调节破骨细胞活性以预防与骨骼相关疾病的方法，但人们对新型抗吸收剂的需求日益增加。在此，我们研究了非编码 RNA 分子，并提出 DLEU1 和 miR-16 作为调节破骨细胞功能的潜在候选物。DLEU1 和 miR-16 靶向破骨细胞生成的早期和晚期的细胞融合，但通过独立的途径发挥作用。DLEU1 的沉默会阻碍融合过程，导致吞噬杯融合方式被阻断，单核前体细胞与多核破骨细胞之间的融合事件减少，而 miR-16 则影响单核细胞向破骨细胞的分化，削弱破骨细胞的形成，但在早期阶段不影响核的数量。另一方面，利用这些非编码 RNA 来构建成熟的破骨细胞对骨吸收具有影响。DLEU1 和 miR-16 都影响形成陷窝的破骨细胞的吸收速度，而不影响被吸收的区域。然而，增加 miR-16 水平的影响更为广泛，也会影响沟槽形成的破骨细胞，导致其比例、速度和被吸收区域减少。这些发现为改善骨骼疾病中的骨破坏提供了新的潜在治疗靶点。
