Effects of Thyroxine (T4), 3,5,3′-triiodo-l-thyronine (T3) and their Metabolites on Osteoblast Differentiation

Abstract

Studies involving human genetic mutations and mutant mouse models have provided irrevocable evidence for a key role for thyroid hormones (THs) in the regulation of skeletal growth. While T3 binds to TH receptors with higher affinity than T4, T4 occupied TH receptors have also been reported in the nucleus under euthyroid conditions raising the possibility that T4 bound nuclear receptors may be biologically relevant in thyroid syndromes with elevated free T4 and reduced T3 levels. We, therefore, evaluated the direct effects of T4, T3, and their metabolites (rT3 and T2) in stimulating osteoblast differentiation using MC3T3-E1 preosteoblasts which do not produce detectable levels of deiodinases. Under serum-free conditions, a 24-h treatment of MC3T3-E1 cells with THs and their metabolites caused a dose-dependent increase in the expression of osteoblast differentiation markers, osterix, and osteocalcin. Circulating concentrations of T3 (~1 ng/ml) and T4 (~30 ng/ml) showed similar potency in stimulating osteoblast differentiation marker expression, while rT3 and T2 were less potent than T3 and T4. Moreover, T3 and T4 treatments elevated the IGF-1 mRNA level suggesting the involvement of IGF-1 signaling in the TH regulation of osteoblast differentiation. We conclude that an elevated T4 level in the absence of T3 may exert stimulatory effects on osteoblast differentiation. The establishment of cell-specific effects of T4 on osteoblasts may provide a strategy to generate T4 mimics that exert skeletal specific effects without the confounding T3 effects on other tissues.

Energy Metabolism in the Bone is Associated with Histomorphometric Changes in Rats with Hyperthyroidism

“…There are also data showing that in vitro thyroid hormones affect the energy metabolism in the bone remodelling process. T4 has been found to induce bone formation, differentiation, and mineralization in osteoblast- or osteoblast-like cells [27, 28]; more importantly, Gouveia et al revealed that T3 acted on the osteoblast-like cell mitochondrial gene ATPase 6 [29]. Although Kanatani et al discovered that T3 directly stimulated osteoclast differentiation [6] and Ma and Dai suggested that T3 stimulated osteoclast differentiation indirectly [30], only a few studies have investigated the effect of T4 on osteoclasts.…”

“…A clinical case–control study has shown that hyperthyroidism can cause net bone loss, decreased bone mineral density (BMD), and osteoporosis and increase the risk for fractures [1]. Both animal and clinical studies have shown that subjects with hyperthyroidism had higher bone resorption rates and bone formation marker levels [2-4] and that excessive levels of thyroid hormones might stimulate both osteoblast and osteoclast differentiation, however, the latter was more predominantly observed [5, 6]. Hyperthyroidism led to a higher frequency of bone remodelling.…”

Integrative analysis of multiomics data identified acetylation as key variable of excessive energy metabolism in hyperthyroidism-induced osteoporosis rats

“…In addition, the thyroid hormone (TH) played a vital role in energy metabolism since high load of TH enhance the metabolism of body substances. It was found that T4 had a positive effect on bone formation, differentiation, and mineralization in osteoblasts [19,20] . Also, excessive T4 levels might promote both osteoclast and osteoblast bioenergetics by strengthening the oxidative phosphorylation-TCA cycle-glycolysis pathway [14] .…”

Endocrine Regulation on Bone by Thyroid

“…IGF-1 mRNA levels were increased in MC3T3-E1 cells after treatment with THs, and the increased levels were positively correlated with TH concentrations. Furthermore, their metabolites, including T2 and rT3, could also promote the increase in IGF-1 mRNA levels ( 46 ) ( Figure 3 ).…”