Background:The role of autophagy in osteocytes is unclear. Results: Suppression of autophagy in osteocytes caused decreases in bone mass and bone remodeling similar to those caused by aging. Conclusion: Autophagy in osteocytes maintains the rate of remodeling and bone mass. Significance: A decline in autophagy in osteocytes may contribute to skeletal aging.

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Background: Iron uptake through the transferrin-dependent pathway is essential for osteoclast differentiation. Results: Knocking down the expression of Steap4, an endosomal ferrireductase, inhibits osteoclast formation and decreases cellular iron and ROS production. Conclusion: Steap4 regulates cellular iron metabolism during osteoclast differentiation. Significance: This work provides new insights into the molecular mechanisms regulating cellular iron metabolism in osteoclast lineage cells.

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.