Microtubule organization and lysosomal secretion are both critical for the activation and function of osteoclasts, highly specialized polykaryons that are responsible for bone resorption and skeletal homeostasis. Here, we have identified a novel interaction between microtubule regulator LIS1 and Plekhm1, a lysosome-associated protein implicated in osteoclast secretion. Decreasing LIS1 expression by shRNA dramatically attenuated osteoclast formation and function, as shown by a decreased number of mature osteoclasts differentiated from bone marrow macrophages, diminished resorption pits formation, and reduced level of CTx-I, a bone resorption marker. The ablated osteoclast formation in LIS1-depleted macrophages was associated with a significant decrease in macrophage proliferation, osteoclast survival and differentiation, which were caused by reduced activation of ERK and AKT by M-CSF, prolonged RANKL-induced JNK activation and declined expression of NFAT-c1, a master transcription factor of osteoclast differentiation. Consistent with its critical role in microtubule organization and dynein function in other cell types, we found that LIS1 binds to and colocalizes with dynein in osteoclasts. Loss of LIS1 led to disorganized microtubules and aberrant dynein function. More importantly, the depletion of LIS1 in osteoclasts inhibited the secretion of Cathepsin K, a crucial lysosomal hydrolase for bone degradation, and reduced the motility of osteoclast precursors. These results indicate that LIS1 is a previously unrecognized regulator of osteoclast formation, microtubule organization, and lysosomal secretion by virtue of its ability to modulate dynein function and Plekhm1.

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Marine mussels tightly adhering to various underwater surfaces inspires human to design adhesives for wet tissue adhesion in surgeries. Characterization of mussel adhesive plaques describes a matrix of proteins containing 3,4-dihydroxyphenylalanine (DOPA), which provides strong adhesion in aquatic conditions. Several synthetic polymer systems have been developed based on this DOPA chemistry. Herein, a citrate-based tissue adhesives (POEC-d) was prepared by a facile one-pot melt polycondensation of two diols including 1,8-octanediol and poly(ethylene oxide) (PEO), citric acid (CA) and dopamine, and the effects of hydrophilic and soft PEO on the properties of adhesives were studied. It was found that the obtained adhesives exhibited water-soluble when the mole ratio of PEO to 1,8-octanediol was 70%, and the equilibrium swelling percentage of cured adhesive was about 144%, and degradation rate was in the range of 1-2 weeks. The cured adhesives demonstrated soft rubber-like behavior. The lap shear adhesion strength measured by bonding wet pig skin was in the range of 21.7-33.7 kPa, which was higher than that of commercial fibrin glue (9-15 kPa). The cytotoxicity tests showed the POEC-d adhesives had a low cytotoxicity. Our results supports that POEC-d adhesives, which combined strong wet adhesion with good biodegradability, acceptable swelling ratio, good elasticity and low cytotoxicity, have potentials in surgeries where surgical tissue adhesives, sealants, and hemostatic agents are used.

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