Direct actions of pituitary hormones on bone
M Zaidi1, L Sun1, K Onigata2 & E Abe2
We have revisited the actions of hormones from the anterior pituitary, notably TSH, on bone and bone cells. Traditionally, the bone loss in hyperthyroidism has been attributed solely to elevated circulating levels of thyroid hormones. The role of TSH, which is reduced in all forms of hyperthyroidism, as well as during thyroxine suppressive therapy for thyroid cancer, has never been investigated. We found that haploinsufficiency of the TSH receptor in mice led to bone loss without affecting thyroid follicular development or circulating thyroid hormone levels. This indicates that TSH has a key role in regulating bone mass, independently of serum thyroid hormones. Homozygotic TSH receptor knock out mice were expectedly hypothyroid, but had low bone mineral densities. An interesting form of focal sclerosis was noted on histology, and there were significant increases in the formation of both osteoblasts and osteoclasts in ex vivo cultures from TSH receptor null and heterozygotic mice. TSH inhibited osteoclast formation and function and reduced the survival of both osteoclast precursors and osteoclasts by enhancing apoptosis. The effect of TSH on osteoclastogenesis was mediated by reduced RANK-L signaling, notably the phosphorylation of JNK and IκBα were inhibited, as were the nuclear translocation of c-jun and p65. In osteoblast cultures, TSH inhibited the osteoblast formation and the expression of the LRP-5 receptor. We believe that TSH plays the role of a primary inhibitor of both components of bone remodeling, resorption and formation. Low TSH levels may therefore contribute to the osteoporosis seen in hyperthyroidism and after thyroxine treatment, as is evidenced by recent epidemiological studies. In addition, studies by Onigata and colleagues show that thyroxine supplemented euthyroid patients with TSH receptor mutations have reduced bone mineral densities establishing a direct role for the TSH receptor in humans. Likewise, we are examining a direct action of FSH, the levels of which rise during the menopause, on skeletal remodeling.