Fibroblastic Stromal Cells Express Receptor Activator of NF-κB Ligand and Support Osteoclast Differentiation

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Abstract
Osteoclast formation in bone is supported by osteoblasts expressing receptor activator of NF‐κB ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF) expression. Numerous osteotropic factors regulate expression levels of RANKL and the RANKL decoy receptor osteoprotegerin (OPG) in osteoblasts, thereby affecting osteoclast differentiation. However, not only is RANKL widely expressed in soft tissues, but osteoclasts have been noted in extraskeletal lesions. We found that cultured skin fibroblastic cells express RANKL, M‐CSF, and OPG messenger (mRNA). Stimulation by 1α,25 dihydroxyvitamin D3 [1,25(OH)2D3] plus dexamethasone (Dex) augmented RANKL and diminished OPG mRNA expression in fibroblastic cells and caused the formation of numerous osteoclasts in cocultures of skin fibroblastic cells with hemopoietic cells or monocytes. The osteoclasts thus formed expressed tartrate‐resistant acid phosphatase (TRAP) and calcitonin (CT) receptors and formed resorption pits in cortical bone. Osteoclast formation also was stimulated (in the presence of Dex) by prostaglandin E2 (PGE2), interleukin‐11 (IL‐11), IL‐1, tumor necrosis factor‐α (TNF‐α), and parathyroid hormone‐related protein (PTHrP), factors which also stimulate osteoclast formation supported by osteoblasts. In addition, granulocyte‐macrophage‐CSF (GM‐CSF), transforming growth factor‐β (TGF‐β), and OPG inhibited osteoclast formation in skin fibroblastic cell‐hemopoietic cell cocultures; CT reduced only osteoclast nuclearity. Fibroblastic stromal cells from other tissues (lung, respiratory diaphragm, spleen, and tumor) also supported osteoclast formation. Thus, RANKL‐positive fibroblastic cells in extraskeletal tissues can support osteoclastogenesis if osteolytic factors and osteoclast precursors are present. Such mesenchymally derived cells may play a role in pathological osteolysis and may be involved in osteoclast formation in extraskeletal tissues.