Mst2 Controls Bone Homeostasis by Regulating Osteoclast and Osteoblast Differentiation

Abstract

Mammalian sterile 20-like kinase 2 (Mst2) plays a central role in the Hippo pathway, controlling cell proliferation, differentiation, and apoptosis during development. However, the roles of Mst2 in osteoclast and osteoblast development are largely unknown. Here, we demonstrate that mice deficient in Mst2 exhibit osteoporotic phenotypes with increased numbers of osteoclasts and decreased numbers of osteoblasts as shown by micro-computed tomography (mCT) and histomorphometric analyses. Osteoclast precursors lacking Mst2 exhibit increased osteoclastogenesis and Nfatc1, Acp5, and Oscar expression in response to receptor activator of NF-kB ligand (RANKL) exposure. Conversely, Mst2 overexpression in osteoclast precursors leads to the inhibition of RANKL-induced osteoclast differentiation. Osteoblast precursors deficient in Mst2 exhibit attenuated osteoblast differentiation and function by downregulating the expression of Runx2, Alpl, Ibsp, and Bglap. Conversely, ectopic expression of Mst2 in osteoblast precursors increases osteoblastogenesis. Finally, we demonstrate that the NF-kB pathway is activated by Mst2 deficiency during osteoclast and osteoblast development. Our findings suggest that Mst2 is involved in bone homeostasis, functioning as a reciprocal regulator of osteoclast and osteoblast differentiation through the NF-kB pathway.

Systematic morphological profiling of human gene and allele function via Cell Painting

“…Recent work examining osteoclast-osteoblast differentiation has suggested that Hippo pathway kinases, such as Mst2, may affect the NF-κB pathway through phosphorylation of IkB proteins, thereby promoting nuclear translocation of NF-κB transcription factors (Lee et al, 2015). TAZ was found to be a direct target of NF-κB transcription factors and its expression is regulated via NF-κB signaling (Cho et al, 2010).…”

miR-218 is involved in the negative regulation of osteoclastogenesis and bone resorption by partial suppression of p38MAPK-c-Fos-NFATc1 signaling: Potential role for osteopenic diseases

“…During the differentiation of osteoclasts from hematopoietic precursors, the monocytic cells must migrate and fuse together to form multinucleated mature osteoclasts [4]. Convincing evidence indicates that osteoclasts exert a critical role in maintaining bone homeostasis by replacing old bones with new bones through coordinating with osteoblasts [5,6]. Therefore, understanding the underlying mechanism involved in osteoclast differentiation and activation processes is urgently needed for the treatment of osteopenic diseases.…”

Hippo signaling protein MST1 regulates osteoclast differentiation by interacting with integrin linked kinase (ILK) and modulating actin structures

“…These results suggest a critical role of Hippo pathway proteins MST1/2 in osteoclast differentiation. Similarly, previous observation has also shown that MST2 KD could increase osteoclast differentiation [20]. However, as MST1 showed a more prominent change than MST2 in our system, we evaluated the Hippo pathway with osteoclast differentiation through MST1.…”