Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures

Abstract

We have shown that the anterior pituitary hormone, thyroidstimulating hormone (TSH), can bypass the thyroid to exert a direct protective effect on the skeleton. Thus, we have suggested that a low TSH level may contribute to the bone loss of hyperthyroidism that has been attributed traditionally to high thyroid hormone levels. Earlier mouse genetic, cell-based, and clinical studies together have established that TSH inhibits osteoclastic bone resorption. However, the direct influence of TSH on the osteoblast has remained unclear. Here, we have used a model system developed from murine ES cells, induced to form mature mineralizing osteoblasts, and show that TSH stimulates osteoblast differentiation primarily through the activation of protein kinase Cδ and the up-regulation of the noncanonical Wnt components frizzled and Wnt5a. We predict that a TSH-induced, fast-forward short loop in bone marrow permits Wnt5a production, which, in addition to enhancing osteoblast differentiation, also stimulates osteoprotegerin secretion to attenuate bone resorption by neighboring osteoclasts. We surmise that this loop should uncouple bone formation from bone resorption with a net increase in bone mass, which is what has been observed upon injecting TSH.

Pituitary-bone connection in skeletal regulation

“…While it inhibits osteoblastogenesis in bone marrow-derived cell cultures, TSH stimulates differentiation and mineralization in murine cell cultures through a Wnt5a-dependent mechanism [67]. Likewise, in vivo, intermittently administered TSH is anabolic in both rats and mice [69,73].…”

“…At least 20 clinical studies have since documented tight and highly reproducible correlations between low TSH levels, bone loss, bone geometry, and fracture risk in patient cohorts across the globe . Evidence also shows that TSH protects the skeleton by exerting anti-resorptive and anabolic actions in rodent models and in people [37,[62][63][64][65][66][67][68][69][70][71].…”

Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling

“…Activation of the TSH receptor (TSHR) on the osteoclast prevents the resorption of bone (4). When administered intermittently, TSH stimulates osteoblastic bone formation and, in rodent models, rescues ovariectomy-induced bone loss (5)(6)(7)(8). In contrast, absence of the TSHR in the global Tshr -/-mouse causes high-turnover osteoporosis (4).…”

“…We and others have shown that, in addition to its known function in stimulating thyroid follicular cells, TSH can act directly on the skeleton (4)(5)(6)(7)(8). Activation of the TSH receptor (TSHR) on the osteoclast prevents the resorption of bone (4).…”

Enhancement of Osteogenic Differentiation by Combination Treatment with 5-azacytidine and Thyroid-Stimulating Hormone in Human Osteoblast Cells

“…While it inhibits osteoblastic differentiations in bone marrow-derived mesenchymal stromal cell cultures, TSH stimulates differentiation and mineralization in murine cell cultures via a Wnt5a-dependent manner. 12) Similarly, intermittently administered TSH showed anabolic effects on bone remodeling in both rats and mice. 13,14) Thus, the effect of TSH may be differentiation according to the differentiation stages.…”