osteoclastogenesis

Osteoclastogenesis is the process by which osteoclasts, the bone-resorbing cells, differentiate from hematopoietic precursors of the monocyte/macrophage lineage. It is a key component of skeletal remodeling, enabling removal of old or damaged bone in concert with osteoblast-mediated formation. Differentiation is driven by signaling from the RANKL–RANK axis and by macrophage colony-stimulating factor (M-CSF).

M-CSF acts through its receptor c-Fms to promote precursor survival and proliferation. RANKL, expressed by osteoblasts and osteocytes, binds RANK on osteoclast precursors to activate NF-κB and MAPK pathways, culminating in induction of the transcription factor NFATc1; c-Fos acts as a key co-regulator. NFATc1 is widely regarded as the master regulator of osteoclastogenesis. Fusion of precursors into multinucleated osteoclasts is facilitated by fusogenic proteins such as DC-STAMP and OC-STAMP and is coordinated by NFATc1 activity. Osteoprotegerin (OPG), a decoy receptor produced by osteoblast lineage cells, inhibits RANKL signaling by sequestering RANKL.

Mature osteoclasts attach to the bone surface and form a sealed resorption lacuna with a ruffled border. They resorb by acidifying the microenvironment and secreting proteolytic enzymes such as cathepsin K and collagenases that degrade bone matrix.

Regulation of osteoclastogenesis is integrated with osteoblast activity in bone remodeling. Excessive osteoclastogenesis contributes to osteoporosis and inflammatory bone diseases, whereas reduced formation can lead to osteopetrosis. Therapeutic strategies include inhibition of RANKL with denosumab and various anti-resorptive agents such as bisphosphonates.

Laboratory studies use markers such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K and in vitro assays with RANKL and M-CSF to model differentiation and resorption.