Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, People's Republic of China.
Department of Biochemistry, Basic Medical College of Shanxi Medical University, Taiyuan, People's Republic of China.
Sci Rep. 2024 Aug 28;14(1):19973. doi: 10.1038/s41598-024-70814-8.
Osteoblasts and osteoclasts play an important role in maintaining the structural integrity of bone tissue, in which osteoclasts degrade bone structure and osteoblasts restore bone tissue. The imbalance of osteoblast and osteoclast function can lead to many bone-related diseases, such as osteoporosis and inflammatory osteolysis. The drug that can both promote bone formation and inhibit bone loss will be able to treat those diseases. In this study, it was found that LMK-235, an selective HDAC4/5 inhibitor, inhibited the differentiation and maturation of osteoclasts by regulating NF-κB and p-Smad2/3 signaling pathways via inhibition of HDAC4. At the same time, we found that LMK-235 promoted osteoblast mineralization by upregulating Runx2 expression via inhibition of HDAC4. In vivo, LMK-235 was able to alleviate lipopolysaccharide (LPS)-induced calvarial osteolysis and promote the repair of bone defects. Taken together, LMK-235 suppresses osteoclast differentiation and promotes osteoblast formation by inhibiting HDAC4. This may provide a valuable treatment for bone diseases caused by abnormal osteoclast bone resorption and osteoblast bone regeneration.
成骨细胞和破骨细胞在维持骨组织结构完整性方面发挥着重要作用，其中破骨细胞降解骨结构，而成骨细胞则修复骨组织。成骨细胞和破骨细胞功能的失衡可导致许多与骨相关的疾病，如骨质疏松症和炎症性溶骨性疾病。能够促进骨形成和抑制骨质流失的药物将能够治疗这些疾病。在这项研究中，发现选择性 HDAC4/5 抑制剂 LMK-235 通过抑制 HDAC4 调节 NF-κB 和 p-Smad2/3 信号通路来抑制破骨细胞的分化和成熟。同时，我们发现 LMK-235 通过抑制 HDAC4 上调 Runx2 表达来促进成骨细胞矿化。在体内，LMK-235 能够减轻脂多糖（LPS）诱导的颅骨骨溶解，并促进骨缺损的修复。总之，LMK-235 通过抑制 HDAC4 抑制破骨细胞分化并促进成骨细胞形成。这可能为异常破骨细胞骨吸收和成骨细胞骨再生引起的骨疾病提供有价值的治疗方法。
