科研之友
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摘要
Takl is a MAPKKK that can be activated by growth factors and cytokines such as RANKL and BMPs and its downstream pathways include NF-kappa B and JNK/p38 MAPKs. Takl is essential for mouse embryonic development and plays critical roles in tissue homeostasis. Previous studies have shown that Takl is a positive regulator of osteoclast maturation, yet its roles in bone growth and remodeling have not been assessed, as mature osteoclast-specific Takl deletion with Cstk-Cre resulted in runtedness and postnatal lethality. Here we generated osteoclast progenitor (monocyte)-specific Takl knockout mice and found that these mice show normal body weight, limb size and fertility, and osteopetrosis with severity similar to that of RANK or RANKL deficient mice. Mechanistically, Takl deficiency altered the signaling of NF-kappa B, p38MAPK, and Smad1/5/8 and the expression of PU.1, MITF, c-Fos, and NFATc1, suggesting that Takl regulates osteoclast differentiation at multiple stages via multiple signaling pathways. Moreover, the Takl mutant mice showed defects in skull, articular cartilage, and mesenchymal stromal cells. Ex vivo Takl-/- monocytes also showed enhanced ability in promoting osteogenic differentiation of mesenchymal stromal cells. These findings indicate that Takl functions in osteoclastogenesis in a cell-autonomous manner and in osteoblastogenesis and chondrogenesis in non-cell-autonomous manners.
