Chen Jin Hong, Shen Chen, Oh Ha Ram, Park Ji Hyun
Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Republic of Korea.
J Mol Endocrinol. 2022 Apr 22;68(4):195-207. doi: 10.1530/JME-21-0213.
During bone formation, mesenchymal progenitor cells mature into bone-forming osteoblasts after undergoing several stages of differentiation. Impaired bone formation is a predominant finding in glucocorticoid (GC)-induced osteoporosis (GIO). Osteoblasts at different stages of maturation can be affected by excessive endogenous or therapeutic GCs. Sex-determining region Y-box 2 (SOX2) is normally expressed in immature osteoblasts, but its overexpression can suppress osteoblast differentiation. This study aimed to evaluate whether GC affects SOX2 expression in osteoblasts, and whether SOX2 contributes to GC-induced inhibition of osteoblast differentiation. Treatment with GCs such as dexamethasone (Dex) or hydrocortisone enhanced SOX2 expression. Silencing SOX2 improved inhibition of GC-induced osteoblast differentiation, whereas SOX2 overexpression decreased mineralized nodule formation and RUNX2 and Osterix expression in MC3T3-E1 cells. On the contrary, when C3H10T1/2 uncommitted mesenchymal stem cells were subjected to SOX2 overexpression, RUNX2 expression increased. As a mechanism of Dex-induced SOX2 upregulation in preosteoblasts, we found that the STAT3 pathway or GC receptor (GR) is involved, using a GR antagonist, STAT3 regulators, and chromatin immunoprecipitation assays. Moreover, mice treated with Dex for 4 weeks showed a notable increase in SOX2 expression in the bones and an increased ratio of procollagen type 1 N-terminal propeptide to osteocalcin in the plasma than in control mice. This study demonstrated that GC enhances SOX2 expression in vitro in osteoblast and in vivo in the mice bone, which affects bone-forming activity differently depending on the differentiation stage of osteoblast-lineage cells. Our results provide new insights into prevention and treatment against impaired bone formation in GIO.
在骨形成过程中，间充质祖细胞在经历几个分化阶段后成熟为成骨的成骨细胞。骨形成受损是糖皮质激素（GC）诱导的骨质疏松症（GIO）的主要表现。不同成熟阶段的成骨细胞会受到内源性或治疗性GC过量的影响。性别决定区Y盒2（SOX2）通常在未成熟的成骨细胞中表达，但其过表达会抑制成骨细胞分化。本研究旨在评估GC是否影响成骨细胞中SOX2的表达，以及SOX2是否促成GC诱导的成骨细胞分化抑制。用地塞米松（Dex）或氢化可的松等GC处理可增强SOX2表达。沉默SOX2可改善GC诱导的成骨细胞分化抑制，而SOX2过表达则减少MC3T3-E1细胞中的矿化结节形成以及RUNX2和osterix表达。相反，当C3H10T1/2未分化的间充质干细胞进行SOX2过表达时，RUNX2表达增加。作为Dex诱导前成骨细胞中SOX2上调的一种机制，我们通过使用GR拮抗剂、STAT3调节剂和染色质免疫沉淀试验发现，STAT3途径或糖皮质激素受体（GR）参与其中。此外，用Dex处理4周的小鼠骨骼中SOX2表达显著增加，血浆中I型前胶原N端前肽与骨钙素的比值高于对照小鼠。本研究表明，GC在体外成骨细胞和体内小鼠骨骼中均增强SOX2表达，这根据成骨细胞系细胞的分化阶段不同地影响骨形成活性。我们的结果为GIO中骨形成受损的预防和治疗提供了新的见解。
