Abstract
Resorptive activity of osteoclasts is important for maintaining bone homeostasis. Endogenous compounds such as oxidized low density lipoprotein (oxLDL) have been shown to disturb this activity. While some studies have investigated the effects of oxLDL on the process of osteoclastogenesis, the underlying mechanism are not fully understood. We show here that oxLDL concentrations of ~10–25 µg protein (0.43–1.0 µM MDA/mg protein) completely blocked the formation of functional osteoclasts. The underlying mechanism implies an inhibition of autophagy that in turn leads to a decreased fusion of cathepsin K (CatK)-loaded lysosomal vesicles with the ruffled border membrane. As result, a lower secretion of CatK and impaired protonation of the resorption lacunae by vacuolar-ATPase (v-ATPase) is observed in the presence of oxLDL. We demonstrate that scavenger receptor A (SR-A) mediates oxLDL effects on osteoclastogenesis and repressing this receptor partially rescued oxLDL effects. Collectively, our data provides an insight into the possible mechanism of oxLDL on osteoclastogenesis suggesting that it does not perturb the packaging of CatK and v-ATPase (V-a3) in the secretory lysosome, but inhibits the fusion of these lysosomes to the ruffled border. The relevance of our findings suggests a distinct link between oxLDL, autophagy and osteoclastogenesis.
Highlights
Cardiovascular disease (CVD) is the most common cause of mortality in the general population
Studies have shown that retention of endogenous compounds such as oxidized low density lipoprotein (oxLDL) can disturb the delicate balance between bone forming cells and bone resorbing cells thereby affecting bone homeostasis and bone remodeling[6,12,13,14,15,16,17]
Because osteoclasts become apoptotic after each resorptive cycle[11], we were more interested in the effects of oxLDL on the process of osteoclastogenesis than on its activity of already formed osteoclasts
Summary
Cardiovascular disease (CVD) is the most common cause of mortality in the general population While several factors such as uremia, inflammation, vascular calcification etc. The intercellular communications between these two cell types must be tightly regulated to maintain bone homeostasis[6], since an increased osteoblast activity would lead to osteopetrosis in the bone and calcification in the vessel walls while an increased osteoclast activity leads to diseases such as osteoporosis or inflammatory arthritis[7]. Osteoclasts are multinucleated cells derived from the monocyte/macrophage lineage and developed by the cell-cell fusion The fusion of these cells are mediated by soluble factors produced by osteoblasts such as the macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)[8,9]. We demonstrate that oxLDL inhibits the process of osteoclastogenesis and the functional activities of osteoclasts by disabling the expression and more importantly, the secretion of CatK through autophagy regulation
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