骨髓基质干细胞（BMSCs）是构成骨髓微环境不可缺少的细胞，通常认为它们参与骨肉瘤（OS）的发展和进展。为了探索在BMSCs中抑制mTORC2信号通路是否能够抑制OS生长和肿瘤引起的骨破坏，我们注射K7M2细胞到基因型为Rictor flox/flox或Prx1-cre; Rictor flox/flox（相同性别）的3个月龄雏鼠的近端胫骨中。 40天后，Prx1-cre; Rictor flox/flox小鼠的骨破坏得到缓解，在X线和微型CT上可见。此外，血清N端前胶原I型前肽（PINP）水平降低，并且体内肿瘤骨形成减少。在体外研究了K7M2与BMSCs之间的相互作用。在肿瘤条件培养基（TCM）中培养的缺乏Rictor的BMSC导致减少的骨增殖和抑制的成骨分化。此外，与对照组相比，在缺乏Rictor的BMSC培养基（BCM）中培养的K7M2细胞显示出较少的增殖、迁移和侵袭，并且成骨活性减弱。然后通过小鼠细胞因子阵列分析了40种细胞因子，并检测到缺乏Rictor的BMSC中降低的CCL2/3/5和白细胞介素16水平。这些结果表明，在BMSC中抑制mTORC2（Rictor）信号通路通过两种机制发挥抗OS效应：（1）通过抑制OS诱导的BMSC增殖和成骨分化，减轻骨破坏；（2）通过减少BMSC分泌的与OS细胞增殖、迁移、侵袭和肿瘤形成的成骨密切相关的细胞因子，从而减弱OS细胞的活性。© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Bone marrow mesenchymal stem cells (BMSCs) are indispensable cells constituting the bone marrow microenvironment that are generally recognized as being involved in the development and progression of osteosarcoma (OS). To explore whether mTORC2 signaling inhibition in BMSCs suppressed OS growth and tumor-caused bone destruction, 3-month-old littermates genotyped Rictor flox/flox or Prx1-cre; Rictor flox/flox (with same gender) were injected with K7M2 cells in the proximal tibia. After 40 days, bone destruction was alleviated in Prx1-cre; Rictor flox/flox mice, as observed on X-ray and micro-CT. This was accompanied by decreased serum N-terminal propeptide of procollagen type I (PINP) levels and reduced tumor bone formation in vivo. Interactions between K7M2 and BMSCs were studied in vitro. Rictor-deficient BMSCs, which were cultured in tumor-conditioned medium (TCM), caused reduced bone proliferation and suppressed osteogenic differentiation. Moreover, compared with the control group, K7M2 cells cultured in BCM (culture medium extracted from Rictor-deficient BMSCs) displayed less proliferation, migration, and invasion, and attenuated osteogenic activity. Forty types of cytokines were then analysed by mouse cytokine array and decreased levels CCL2/3/5 and interleukin 16 were detected in Rictor-deficient BMSCs. These results suggested that inhibition of mTORC2 (Rictor) signaling pathway in BMSCs exerted anti-OS effects through two mechanisms: (1) by suppressing the proliferation and osteogenic differentiation of BMSCs induced by OS to alleviate bone destruction; (2) by reducing the secretion of cytokines by BMSCs, which are closely related to OS cell growth, migration, invasion, and tumorigenic osteogenesis.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.