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.

No abstract

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.

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.

Genetic studies in human and mice have pinpointed an essential role of Notch signaling in osteoblast and osteoclast differentiation during skeletal development and bone remodeling. However, the factors and pathways regulating Notch activation in bone cells remain largely unknown. In this in vitro study, we have provided evidence that two of the TspanC8 subfamily members of tetraspanins, Tspan-5 and Tspan-10, are up-regulated during osteoclast differentiation and knockdown of their expression by shRNAs dramatically inhibits osteoclastogenesis. Loss of Tspan-5 and Tspan-10 in osteoclast lineage cells results in attenuation of ADAM10 maturation and Notch activation. Therefore, these two tetraspanins play a critical role in osteoclast formation, at least in part, by modulating Notch signaling pathway.

Key Points High expression of MAF protein in myeloma due to t(14;16) translocation confers innate resistance to PIs. PIs prevent GSK3-mediated degradation of MAF protein, which further augments the resistance to PIs in t(14:16) myeloma.

In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.

Carfilzomib, the next generation of proteasome inhibitor, may increase osteoblast-related markers in patients with multiple myeloma, but the molecular mechanism of its effect on mesenchymal stem cell differentiation to osteoblasts remains unknown. Herein, we demonstrated that carfilzomib significantly promoted mesenchymal stem cell differentiation into osteoblasts. In osteoprogenitor cells and primary mesenchymal stem cells from patients with myeloma, carfilzomib induced increases in alkaline phosphatase activity, matrix mineralization, and calcium deposition via Wnt-independent activation of β-catenin/TCF signaling. Using affinity pull-down assays with immunoblotting analysis and immunofluorescence, we found that carfilzomib induced stabilization of both free and active forms of β-catenin in a time- and dose-dependent manner that was not associated with β-catenin transcriptional regulation. Nuclear translocation of β-catenin protein was associated with TCF transcriptional activity that was independent of the effects of GSK3β-activation and of signaling induced by 19 Wnt ligands, 10 Frizzled receptors, and LRP5/6 co-receptors. Blocking activation of β-catenin/TCF signaling by dominant negative TCF1 or TCF4 attenuated carfilzomib-induced matrix mineralization. Thus, carfilzomib induced osteoblast differentiation via Wnt-independent activation of the β-catenin/TCF pathway. These results provide a novel molecular mechanism critical to understanding the anabolic role of carfilzomib on myeloma-induced bone disease.