Here find an interesting review of what is known of the role of iron metabolism in osteoporosis, the progressive loss of bone mineral density that occurs with age. Bone tissue is constantly remodeled throughout life, the bone extracellular matrix deposited by osteoblast cells and broken down by osteoclast cells. The loss of strength and increasing fragility of bone in older people arises because of a growing imbalance between osteoblast and osteoclast activity, favoring the osteoclasts. Thus there are many possible ways one could in principle intervene in this problem, most of these approaches not even touching on the underlying causes of the condition, but rather trying to enhance osteoblast activity or inhibit osteoclast activity in some way. As researchers here note, aspects of iron metabolism are in this list of targets for intervention.
Osteoclast-mediated bone resorption is a tightly regulated process essential for maintaining skeletal integrity. Hyperactive osteoclasts are recognized as key contributors to excessive bone loss in conditions such as osteoporosis. Osteoclasts possess a unique ability to resorb bone matrix by releasing hydrolytic enzymes and secreting acid into a specialized extracellular compartment known as the ruffled border. This resorptive function is heavily reliant on two cellular organelles: lysosomes and mitochondria. Lysosomes create an acidic environment via a vacuolar proton pump (v-ATPase), which is essential for protease production. These acidic components, including protons and proteases, are delivered into the ruffled border to degrade the aged bone matrix. Meanwhile, this bone resorption process is highly energy demanding, in which mitochondria serve as the primary energy source. Additionally, mitochondria also provide energy to lysosomes to ensure that they are well functioned in producing and releasing acidic components.
A central player linking mitochondria and lysosomes in osteoclast-mediating bone resorption is iron. Lysosomes act as major iron uptake and recycling centers, regulating iron metabolism by controlling its trafficking, storage, and redistribution. Lysosomal acidification is essential for iron uptake, reducing ferric iron (Fe3+) to ferrous iron (Fe2+), which is then released into the cytoplasm and incorporated into the labile iron pool (LIP) for utilization, storage, or export. Subsequently, mitochondria are the primary sites for iron utilization, facilitating processes, such as oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC) pathway, to generate energy and reactive oxygen species. In the context of bone homeostasis, clinical observations dating back to the early 1900s have established a connection between iron overload and excessive bone loss, underscoring the pivotal role of iron in maintaining bone homeostasis.
Building on these insights, a deeper understanding of the interactions among lysosomes, mitochondria, and iron, particularly in the context of osteoclasts and osteoporosis, is urgently needed. This review focuses on the roles of the lysosome-iron-mitochondria axis in osteoclast function and its implications for osteoporosis. We first examining the evidence supporting the pivotal function of lysosomes in regulating iron homeostasis in osteoclasts, as well as their possible involvement of iron in lysosomal biogenesis and function. Next, we summarize current knowledge on iron utilization in mitochondria and its implications for osteoclast activity. Following this, we explore emerging mechanisms underlying lysosome-mitochondria crosstalk in iron metabolism. Finally, we discuss how dysregulation of the lysosome-iron-mitochondria axis contributes to osteoclast dysfunction and highlight the potential therapeutic strategies targeting this axis for osteoporosis treatment.
Link: https://doi.org/10.34133/research.0840
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