Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.

Abstract

Liver serine-threonine kinase B1 (LKB1) is a tumor suppressor that has been linked to many types of tumors. However, the role of LKB1 in cartilaginous tumorigenesis is still poorly understood. In this study, we find that cartilage-specific, tamoxifen-inducible Lkb1 knockout results in multiple enchondroma-like lesions adjacent to the disorganized growth plates. We showed that chondrocytes retain an immature status caused by loss of Lkb1, which may lead to the dramatic expansion of growth-plate cartilage and the formation of enchondroma-like lesions. Additionally, increased mammalian target of rapamycin complex 1 (mTORC1) activity is observed in the Lkb1 conditional knockout (cKO) chondrocytes, and rapamycin (mTORC1 inhibitor) treatment significantly alleviates the expansion of growth-plate cartilage and eliminates the enchondroma-like lesions in Lkb1 cKO mice. Thus, our findings indicate that loss of Lkb1 leads to the expansion of chondrocytes and the formation of enchondroma-like lesions during postnatal cartilage development, and that the up-regulated mTORC1-signaling pathway is implicated in this process. Our findings suggest that modulation of LKB1 and related signaling is a potential therapy in cartilaginous tumorigenesis.-Zhou, S., Li, Y., Qiao, L., Ge, Y., Huang, X., Gao, X., Ju, H., Wang, W., Zhang, J., Yan, J., Teng, H., Jiang, Q. Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.

• Authors: Sheng Zhou, Yixuan Li, Liang Qiao, Yuxiang Ge, Xiaojing Huang, Xiang Gao, Huangxian Ju, Wei Wang, Junfeng Zhang, Jun Yan, Huajian Teng, Qing Jiang
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 8 Pg. 9476-9488 (08 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 31091421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Serine-Threonine Kinases
• Stk11 protein, mouse
• AMP-Activated Protein Kinases
• Sirolimus

Topics

• AMP-Activated Protein Kinases
• Animals
• Blotting, Western
• Cartilage (drug effects, metabolism, pathology)
• Cells, Cultured
• Chondrocytes (cytology, metabolism)
• Chondrogenesis (drug effects)
• Chondroma (drug therapy, metabolism, pathology)
• Female
• Fluorescent Antibody Technique
• Growth Plate (cytology, metabolism)
• In Situ Nick-End Labeling
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction (genetics, physiology)
• Sirolimus (therapeutic use)
• Tomography, X-Ray Computed