Thyroid Hormone

 Lithium can inhibit thyroid hormone.

Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis.

"Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, . ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. FGFR3 is a T(3)-target gene in chondrocytes.  T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated."

" T3 stimulates chondrogenesis in cultured ATDC5 cells by inhibiting cell proliferation and stimulating the onset of hypertrophic chondrocyte differentiation. The antiproliferative effects of T3 occurred during the first 6 d of ATDC5 cell culture, and differentiation progressed until the onset of terminal hypertrophic chondrocyte differentiation by 21 d in T3-treated cells. T3 stimulation of FGFR1 and FGFR2 in ATDC5 cells undergoing chondrogenesis occurred until d 12, but stimulation of FGFR3 by T3 was greater and persisted until d 21, coinciding with the period in which T3 inhibited chondrocyte proliferation and advanced the onset of hypertrophic differentiation. "

"thyrotoxicosis[overactivity of the thyroid gland] leads to accelerated growth and advanced bone age but causes short stature because of premature growth-plate fusion"

Evaluation of the interaction between thyroid hormone and the sympathetic nervous system, via alpha 2 adrenoceptors, on the regulation of bone growth and maturation

"Bone remodeling is under control of the central nervous system (SNC), with the sympathetic nervous system (SNS) acting as the peripheral effector.  The SNS negatively regulates bone mass, acting exclusively via beta 2-adrenoceptor (B2-AR), which is expressed in osteoblasts. Mice with double gene inactivation of the adrenoceptor alpha2A and alpha2C (a2A /a2C -AR-/-) present a phenotype of high bone mass (HBM), in spite of presenting chronic sympathetic hyperactivity and intact B2-AR. These knockout (KO) mice are resistant to the thyroid hormone (TH)-induced osteopenia. Mice with single inactivation of a2A-AR or a2C-AR are resistant to the lower longitudinal bone growth induced by thyrotoxicosis[overactivation of the thyroid gland]. By immunohistochemistry, we detect that both a2A-AR and a2C-AR are expressed in the bone tissue, in the chondrocytes of the reserve and hypertrophic zones of the epiphyseal growth plates (EGP) and in the hypertrophic chondrocytes of the secondary ossification centers of mice. (i) B2-AR is not the sole adrenoceptor involved in the control of bone metabolism and that (ii) the SNS interacts with TH to regulate not only the bone mass, but also the longitudinal bone growth. (i) a2A-AR and/or a2C-AR present an important role in mediating the actions of the SNS in the skeleton and that (ii) these receptors are involved in the TH-SNS interaction to regulate bone metabolism, growth and development. In the present project, we aim to (i) evaluate if the isolated inactivation of a2A-AR and a2C-AR and if the double inactivation of these receptors interfere in the longitudinal bone growth and in the endochondral and intramembranous ossificafication; (ii) characterize the phenotype of the EGP of a2A-AR-/-, a2C-AR-/- and a2A /a2C -AR-/- mice; (iii) evaluate if the action of TH on bone longitudinal growth depends on a2A-AR and/or a2C-AR, analyzing the effect of TH on the EGP structure and on bone growth of a2A-AR-/-, a2C-AR-/- and a2A /a2C -AR-/- mice; (iv) analyze if known pathways of TH action in the EGP (GH/IGF-1 and Wnt/Beta-catenine pathways) are affected by the isolated inactivation of a2A-AR or a2C-AR or by the double inactivation of these receptors (a2A/C-AR-/-); (v) evaluate if the TH action in the endochondral and intramembranous ossification depends on a2A-AR and/or a2C-AR. "