Copper homeostasis and organelle-dependent mechanisms in bone metabolism: implications for osteoporosis therapy
Abstract
Background: Osteoporosis is a prevalent metabolic bone disorder driven by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and current pharmacological options remain limited by adverse effects and incomplete mechanistic targeting. Copper, an essential trace element, has long been linked to bone mineral density through population-level dietary surveys, but whether and how copper mechanistically shapes osteoblast and osteoclast function at the subcellular level has not been systematically reviewed.
Methods: We synthesised genetic, clinical, and cell-biological evidence-including copper-transporter mutation models (Menkes and Wilson disease), organelle-specific trafficking studies, and mechanistic work on copper-dependent enzymes and chaperones-to construct an organelle-resolved account of copper handling in bone cells, extending beyond the mitochondria and trans-Golgi network to include the endoplasmic reticulum and the lysosomal/endosomal system.
Results: Copper regulates bone metabolism through distinct, organelle-specific, and cell-type-specific mechanisms. In mitochondria, physiological copper supports oxidative phosphorylation and osteogenesis, whereas copper overload can trigger cuproptosis, a mechanistically distinct form of cell death mediated by FDX1-dependent aggregation of lipoylated tricarboxylic acid cycle proteins; whether this pathway selectively affects osteoclasts remains an open, and in part contested, question,…
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