Thyroid hormones enhance osteoclast formation and their excess is an important cause of secondary osteoporosis. 3,5,3'-Triiodo-L-thyronine (T3) induced the mRNA expression of receptor activator of nuclear factor-kappaB ligand (RANKL), which is a key molecule in osteoclast formation, in primary osteoblastic cells (POB). This effect was amplified in the copresence of 1alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3). Although T3 alone did not induce octeoclasts in coculture of bone marrow cells with POB, T3 enhanced 1,25(OH)(2)D-3-induced osteoclast formation. Thyroxine (T4) also enhanced 1,25(OH)(2)D-3-induced osteoclast formation. These data suggested that T4 was locally metabolized to T3 for its action, since T4 is a prohormone with little hormonal activity. The mRNA expression of type-2 iodothyronine deiodinase (D2), which is responsible for maintaining local T3 concentration, was induced by 1,25(OH)(2)D-3 dose-and time-dependently. Our data would facilitate our understanding of the mechanism of osteoclast formation by thyroid hormones and suggest a novel interaction between thyroid hormones and 1,25(OH)(2)D-3. (C) 2002 Elsevier Science (USA).