Thyroid Stimulating Hormone (TSH) Protects Against Osteoporosis through AMPK Signaling Pathway in Osteoclasts I

It has been believed that osteoporosis associated with hyperthyroidism due to elevated thyroxine level. But patients with subclinical hyperthyroidism, decline in the level of thyroid stimulating hormone (TSH) alone, are at equal risk of osteoporosis. Research has shown that there is thyroid-stimulating hormone receptor (TSHR) on the osteoclast, but whether TSH regulates osteoclast directly and its mechanisms are still not be stated clearly. In this study, in combination of in vivo and in vitro, we took the osteoclast precursor cell conditional and systemic knockout TSHR mouse models to study the effects of TSHR knockout on bone metabolism in mice and the changes of osteoclast differentiation and function in vitro. Transcriptomics was used to screen the differential genes and signal pathways, and the in vitro experiments were verified. We found that Tshr flox/ flox Lyz2-Cre (TSHR MKO) mice display decreased femoral biomechanics and bone density, damaged bone microstructure. Serum bone resorption marker CTX-I was significantly increased, accompanied by an increase in the number of osteoclasts in bone sections in TSHR MKO mice. The percentage of CD11b+ in TSHR knockout mice was decreased compared with control littermates. Osteoclasts from Tshr -/- mice had stronger osteoclast differentiation and acid secretion ability. In vitro cell experiments confirmed TSH effecting osteoclast differentiation and function by activation of AMPK signaling pathway. In conclusion, TSH inhibits osteoclast differentiation and bone resorption by activating AMPK signaling pathway, increases bone mass, and has osteoprotective effect. This will provide a reference for the diagnosis and treatment of osteoporosis, especially thyroid function related bone metabolism bnormalities. TSH structural analogues or AMPK activators are expected to provide new ideas for the development of drugs for the prevention and treatment of osteoporosis.