Spectrum and functions of ion channels and transporters in osteoclasts

Osteoclasts are essential for bone resorption and interact with osteoblasts during bone remodeling. Ion channels and transporters located in the ruffled border or intracellular vesicles coordinate the transport of various ions and substrates, which is fundamental to the primary functions of osteoclasts. Numerous channels and transporters are implicated in bone metabolic disorders and genetic diseases. Among these, the voltage-gated chloride channel 7 (ClC-7) and vacuolar proton ATPases (V-ATPase) represent the most well-characterized examples in osteoclasts. Using the classification system of the Transporter Classification Database, we reviewed nearly 90 osteoclastic ion channels and transporters, categorizing them into six groups: ATPases, cation channels, anion channels, complex transporters, organic substance transporters, and ATP-binding cassette transporters. We summarized recent advances in their subcellular localization, transported substrates, associated diseases, and physiological roles in relevant biological functions and signaling pathways. Notably, transporters for hydrogen, chloride, phosphate, and calcium are particularly critical for osteoclast function. We also reviewed therapeutic candidates targeting these ion channels and discussed strategies for their future development. As transcriptome and other advanced techniques have identified more channels and transporters in osteoclasts, the diversity and unexplored functions of these molecules may exceed previous understanding. Increased attention to their widespread distributions and interactions could reveal new therapeutic targets for osteoclast-related and other bone disorders.