Endocrine Abstracts (2006) 11 OC51

TSH receptor action in osteoblasts and osteoclasts in vitro

E Murphy1, AJ Williams1, TM Galliford1, S Costagliola2, G Vassart2, JHD Bassett1 & GR Williams1


1Molecular Endocrinology Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom; 2Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.


Recent studies suggest TSH inhibits bone remodeling, indicating that TSH deficiency rather than thyroid hormone excess could cause bone loss in thyrotoxicosis. The findings predict that TSH receptor (TSHR) stimulating antibodies (TSHRAb) should inhibit bone turnover, whereas Graves’ disease patients exhibit high bone turnover with increased fracture susceptibility. We characterized TSH-action in primary human and mouse osteoblasts and osteoclasts, and explored whether a paracrine pathway involving TSH or thyrostimulin (a novel high-affinity TSHR agonist) could account for TSH-action in bone. TSHR expression was identified by RT-PCR in human and mouse osteoblasts and osteoclasts. TSH-alpha was expressed only in human osteoblasts, but TSH-beta was undetectable in all cells. Thyrostimulin-alpha was expressed in osteoblasts and osteoclasts from both species, whereas thyrostimulin-beta was only expressed in human osteoblasts and osteoclasts. Treatment of osteoblasts with TSH (10–100 U/ml; 7–28 days) did not alter alkaline phosphatase activity or bone nodule mineralization. Treatment of osteoclasts with TSH (100U/ml; 12 days) resulted in 2.8-fold fewer resorption pits formed on dentine slices (control 116±5 vs TSH-treated 41±1.2 pits/slice, P<0.0001) and 2.7-fold fewer osteoclasts (control 225±19 vs TSH-treated 84±9 TRAP+ve cells/well, P<0.001). Treatment of mature osteoblasts or osteoclasts with TSH (10–100 U/ml) or four monoclonal TSHRAb failed to induce cAMP, the canonical mediator of TSH-activated TSHR signaling. Thus, although both osteoblasts and osteoclasts expressed TSHR mRNA, only osteoclasts responded to TSH. There was no evidence of a TSH paracrine pathway indicating that skeletal actions of TSH in vivo must result from circulating TSH, although activation of TSHR in human bone may also involve locally produced thyrostimulin. The lack of cAMP response to TSH or TSHRAb in mature osteoclasts suggests (a) the TSHR acts via an alternative pathway or (b) TSH effects on osteoclast numbers and resorption pits reflect its early actions on progenitor cells to regulate osteoclast recruitment and differentiation.

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