Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss

Abstract

We recently described the direct effects of thyroid-stimulating hormone (TSH) on bone and suggested that the bone loss in hyperthyroidism, hitherto attributed solely to elevated thyroid hormone levels, could at least in part arise from accompanying decrements in serum TSH. Recent studies on both mice and human subjects provide compelling evidence that thyroid hormones and TSH have the opposite effects on the skeleton. Here, we show that TSH, when injected intermittently into rodents, even at intervals of 2 weeks, displays a powerful antiresorptive action in vivo. By virtue of this action, together with the possible anabolic effects shown earlier, TSH both prevents bone loss and restores the lost bone after ovariectomy. Importantly, the osteoclast inhibitory action of TSH persists ex vivo even after therapy is stopped for 4 weeks. This profound and lasting antiresorptive action of TSH is mimicked in cells that genetically overexpress the constitutively active ligand-independent TSH receptor (TSHR). In contrast, loss of function of a mutant TSHR (Pro 3 Leu at 556) in congenital hypothyroid mice activates osteoclast differentiation, confirming once again our premise that TSHRs have a critical role in regulating bone remodeling.osteoclast ͉ osteoporosis ͉ pituitary ͉ osteoblast ͉ bisphosphonate C linical data available since von Recklinghausen's first description of thyrotoxic bone disease, the strong correlation between fracture risk and serum thyroid-stimulating hormone (TSH), recent evidence that TSH receptor (TSHR) polymorphisms are associated with low bone mass, and evidence that bone loss occurs in patients with subclinical hyperthyroidism with normal and low TSH levels all support a role for low TSH in the pathogenesis of hyperthyroid osteoporosis, hitherto attributed solely to high circulating levels of thyroid hormones (1-4).Evidence supporting this premise comes in parallel from genetically manipulated mice lacking receptors for either TSH or thyroid hormones (5, 6). We demonstrated that TSHR deficiency induces a high-turnover osteoporosis, with elevated bone formation and resorption even in TSHR haploinsufficient mice that have normal thyroid function. We found that in ex vivo cell cultures continually exposed to TSH, both osteoblastic bone formation and osteoclastic bone resorption were suppressed. Although these studies point to a primary function for TSH in skeletal homeostasis, data have reestablished a role for the two thyroid hormone receptor (TR) isoforms, TR␣ and TR␤ (6). The deficiency of TR␣ induces osteosclerosis in adult mice, whereas hyperthyroid TR␤-null mice display osteopenia despite high circulating TSH levels (6). Thus, evidence from human and mouse studies underscore the paradigm that both thyroid hormone excess and low TSH levels contribute to hyperthyroid bone loss (7).Hyperthyroidism can arise from adenomatous or inflammatory diseases of the thyroid or from overzealous replacement with thyroid hormones. Hyperthyroidism is Ϸ10-fold more common in women, with an incidence of 1 in 1,000...

Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

“…This means that the FSH antibody, administered at a "skeletally active dose," yet to be determined for humans, might potentially spare an otherwise failing ovary during menopause. We have shown likewise that recombinant human TSH, administered intermittently at low, skeletally active doses, prevents ovariectomy-induced bone loss without affecting thyroid function (18). This suggests that pituitary hormones might generally affect the skeleton with remarkable sensitivity, a putative biological advantage that could potentially be harnessed therapeutically.…”

Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways

“…(36) To examine whether CADPE inhibits osteoclastogenesis in vivo, we used the ovariectomized mouse model to mimic menopause-induced bone loss in women. (36) The uterine weight data showed that the ovariectomy operation was successful ( Supplemental Fig. 4).…”

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

“…(37) To examine whether MA prevents OVX-induced bone loss, we used the OVX mouse model to mimic menopause-induced bone loss in women. (37) Figure 3A, B shows a markedly decline in bone volume and trabecular number and an increase in trabecular space at the lumbar spine when OVX mice were compared with sham-operated controls. Treatment of OVX mice with MA significantly prevented the OVX-induced bone loss, as measured by different parameters (Fig.…”