Learning Objectives:

Bone is a highly dynamic organ, which is maintained by a balance between bone-resorbing osteoclasts and bone-forming osteoblasts. Increased osteoclast activity shifts the balance toward bone resorption, cause bone destructive diseases such as rheumatoid arthritis and periodontitis. Ectopic induction of receptor activator of nuclear factor kappa-B ligand (RANKL), a regulator of osteoclast differentiation, leads abnormal osteoclastogenesis. For example, in rheumatoid arthritis, synoviocyte is known as a major source of RANKL.

Cholesteatoma is a non-neoplastic lesion arising in middle ear, which consists of hyper keratinizing epithelial layer and fibrous connective tissue. Due to its bone destructive character, it can cause severe complications. However the mechanism of the bone destruction by cholesteatoma remains to be elucidated.

In this study, we established cholesteatoma-like mass composed of mouse ear pinna-derived keratinocytes and fibroblasts on the calvarial bone of mouse. Histological analysis revealed the experimental mass lesion induced osteoclastogenesis on the bone surface. In addition, we succeeded in establishing an in vitro coculture system of keratinocytes, fibroblasts and osteoclast precursors, and found that keratinocytes stimulate the induction of RANKL in fibroblasts, which leads to osteoclastogenesis.

Thus,this study demonstrates that interatction between keratinocytes and fibroblasts is involved in the differentiation of osteoclasts, which may provide the molecular vasis of a new therapeutic strategy for cholesteatoma-induced bone destruction.