Lack of Myosin X Enhances Osteoclastogenesis and Increases Cell Surface Unc5b in Osteoclast-Lineage Cells

Abstract

Normal bone mass is maintained by balanced bone formation and resorption. Myosin X (Myo10), an unconventional “myosin tail homology 4‐band 4.1, ezrin, radixin, moesin” (MyTH4‐FERM) domain containing myosin, is implicated in regulating osteoclast (OC) adhesion, podosome positioning, and differentiation in vitro. However, evidence is lacking for Myo10 in vivo function. Here we show that mice with Myo10 loss of function, Myo10m/m, exhibit osteoporotic deficits, which are likely due to the increased OC genesis and bone resorption because bone formation is unchanged. Similar deficits are detected in OC‐selective Myo10 conditional knockout (cko) mice, indicating a cell autonomous function of Myo10. Further mechanistic studies suggest that Unc‐5 Netrin receptor B (Unc5b) protein levels, in particular its cell surface level, are higher in the mutant OCs, but lower in RAW264.7 cells or HEK293 cells expressing Myo10. Suppressing Unc5b expression in bone marrow macrophages (BMMs) from Myo10m/m mice by infection with lentivirus of Unc5b shRNA markedly impaired RANKL‐induced OC genesis. Netrin‐1, a ligand of Unc5b, increased RANKL‐induced OC formation in BMMs from both wild‐type and Myo10m/m mice. Taken together, these results suggest that Myo10 plays a negative role in OC formation, likely by inhibiting Unc5b cell‐surface targeting, and suppressing Netrin‐1 promoted OC genesis. © 2019 American Society for Bone and Mineral Research.

The osteoclast cytoskeleton – current understanding and therapeutic perspectives for osteoporosis

“…These results were confirmed by shRNAs-mediated Myo10 silencing in primary mouse osteoclasts (Box 3), which also showed that osteoclast differentiation was affected (Tasca et al, 2017). In contrast to these reports, a recent study found that Myo10 KO osteoclasts differentiated more efficiently (Wang et al, 2019). The actual bone resorption activity of was not assessed, but the serum of the mice contained high levels of bone resorption marker deoxypyridinoline, suggesting Myo10 KO osteoclasts were active in vivo (Wang et al, 2019).…”

“…In contrast to these reports, a recent study found that Myo10 KO osteoclasts differentiated more efficiently (Wang et al, 2019). The actual bone resorption activity of was not assessed, but the serum of the mice contained high levels of bone resorption marker deoxypyridinoline, suggesting Myo10 KO osteoclasts were active in vivo (Wang et al, 2019). Of note, Myo10 KO osteoclasts derived from The function of kinesins, microtubule-associated motors, is mostly unstudied in osteoclasts thus far.…”

Myosin X Interaction with KIF13B, a Crucial Pathway for Netrin-1-Induced Axonal Development

“…We then evaluated axonal growth and midline crossing in control and MyoX-KO cortical neurons. MyoX-KO cortical neurons were achieved by IUE of Cre-GFP or GFP (as a control) into the neocortex of Myo X f/f embryos (at E15.5; Wang et al, 2019 ); and the electroporated brain samples were examined at P7, a critical time window for cortical neuronal axon growth and midline crossing ( Tagawa and Hirano, 2012 ; Fenlon and Richards, 2015 ). To our surprise, axons of Myo X-KO (Cre-GFP + ) neurons crossed the midline, and their lengths were comparable to those of control axons ( Fig.…”

“…Myo X f/f mice were generated as previously described ( Wang et al, 2019 ), and Netrin-1 floxed (NTN1 f/f ) mice were kindly provided by Yu-Qiang Ding (Fudan University, Shanghai, China). All the mouse lines indicated above were maintained on a C57BL/6 background for more than six generations.…”

Thermosensitive nanoparticle of mPEG-PTMC for oligopeptide delivery into osteoclast precursors

“…[7][8][9][10] With further studies, researchers have developed an oligopeptide that can significantly reduce and inhibit the osteoclastic ability of bone marrowderived macrophages (BMMs), and achieve reduce excessive bone absorption. 11,12 In this study, we designed a drug delivery system that can fully and effectively deliver these molecules to BMMs. This will improve the precision and potency of the treatment.…”