Osteoclast

Osteoclasts are large, multinucleated cells responsible for bone resorption, a key part of the bone remodeling cycle. They arise from hematopoietic stem cells of the monocyte/macrophage lineage, and their differentiation requires macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-Β ligand (RANKL). RANKL is produced by osteoblasts and stromal cells, while osteoprotegerin (OPG) acts as a decoy receptor to limit signaling. Mature osteoclasts express enzymes such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K, and they form by fusion of precursors into multinucleated cells that attach to mineralized bone via integrins, notably αvβ3.

Resorption occurs at a specialized resorption lacuna called Howship's lacunae. The osteoclast forms a sealing zone and a ruffled border, creating an isolated microenvironment. It acidifies this space with vacuolar-type H+-ATPases and chloride channels to dissolve hydroxyapatite, and it secretes proteolytic enzymes, including cathepsin K and matrix metalloproteinases, to degrade the organic matrix, predominantly type I collagen. After resorption, the cell detaches and may undergo apoptosis or recycle its components.

Significance and regulation: Osteoclast activity is balanced with osteoblast-mediated bone formation. Disruptions in RANKL–RANK–OPG signaling, aging, or hormonal changes can increase resorption, contributing to osteoporosis. Conversely, impaired osteoclast function causes osteopetrosis due to deficient bone resorption. Therapeutic approaches to limit bone loss include bisphosphonates and denosumab, a monoclonal antibody against RANKL.