NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China.
College of Basic Medical Sciences, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Tianjin, 300070, China.
Stem Cell Res Ther. 2022 Jun 28;13(1):278. doi: 10.1186/s13287-022-02958-1.
Oncostatin M receptor (OSMR), as one of the receptors for oncostatin M (OSM), has previously been shown to mediate the stimulatory role of OSM in osteoclastogenesis and bone resorption. However, it remains to be clarified whether and how OSMR affects the differentiation of osteoblasts.
The expression level of OSMR during osteoblast and adipocyte differentiation was examined. The role of OSMR in the differentiation was investigated using in vitro gain-of-function and loss-of-function experiments. The mechanisms by which OSMR regulates bone cell differentiation were explored. Finally, in vivo function of OSMR in cell fate determination and bone homeostasis was studied after transplantation of OSMR-silenced bone marrow stromal cells (BMSCs) to the marrow of ovariectomized mice.
OSMR was regulated during osteogenic and adipogenic differentiation of marrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. OSMR suppressed osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. Mechanistic investigations showed that OSMR inhibited extracellular signal-regulated kinase (ERK) and autophagy signaling. The downregulation of autophagy, which was mediated by ERK inhibition, suppressed osteogenic differentiation of progenitor cells. Additionally, inactivation of ERK/autophagy signaling attenuated the stimulation of osteogenic differentiation induced by Osmr siRNA. Furthermore, transplantation of BMSCs in which OSMR was silenced to the marrow of mice promoted osteoblast differentiation, attenuated fat accumulation and osteoclast differentiation, and thereby relieved the osteopenic phenotype in the ovariectomized mice.
Our study has for the first time established the direct role of OSMR in regulating osteogenic differentiation of marrow stromal progenitor cells through ERK-mediated autophagy signaling. OSMR thus contributes to bone homeostasis through dual regulation of osteoblasts and osteoclasts. It also suggests that OSMR may be a potential target for the treatment of metabolic disorders such as osteoporosis.
孤啡肽受体（OSMR）作为孤啡肽 M（OSM）的受体之一，先前已被证明可介导 OSM 在破骨细胞生成和骨吸收中的刺激作用。然而，OSMR 是否以及如何影响成骨细胞的分化仍有待阐明。
检测了成骨细胞和脂肪细胞分化过程中 OSMR 的表达水平。利用体外功能获得和功能丧失实验研究了 OSMR 在分化中的作用。探讨了 OSMR 调节骨细胞分化的机制。最后，通过将沉默 OSMR 的骨髓基质细胞（BMSC）移植到去卵巢小鼠的骨髓中，研究了 OSMR 在细胞命运决定和骨稳态中的体内功能。
OSMR 在骨髓基质祖细胞的成骨和成脂分化过程中受到调节，并在去卵巢小鼠的骺板中增加。OSMR 抑制祖细胞的成骨分化并刺激其成脂分化。机制研究表明，OSMR 抑制细胞外信号调节激酶（ERK）和自噬信号。ERK 抑制介导的自噬下调抑制了祖细胞的成骨分化。此外，ERK/autophagy 信号的失活减弱了 Osmr siRNA 诱导的成骨分化刺激。此外，将沉默 OSMR 的 BMSC 移植到小鼠骨髓中可促进成骨细胞分化，减少脂肪堆积和破骨细胞分化，从而缓解去卵巢小鼠的骨质疏松表型。
本研究首次确立了 OSMR 通过 ERK 介导的自噬信号直接调节骨髓基质祖细胞成骨分化的作用。因此，OSMR 通过对成骨细胞和破骨细胞的双重调节，有助于骨稳态。这也表明 OSMR 可能是治疗骨质疏松症等代谢紊乱的潜在靶点。
