Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism.

Thyroid hormone (TH) is important for tissue repair because it regulates cellular differentiation. Intrahepatic TH activity is controlled by both serum TH levels and hepatic deiodinases. TH substrate (T4) is converted into active hormone (T3) by deiodinase 1 (D1) but into inactive hormone (rT3) by deiodinase 3 (D3). Although the relative expressions of D1 and D3 are known to change during liver injury, the cell types and signaling mechanisms involved are unclear. We evaluated the hypothesis that changes in hepatic deiodinases result from repair-related activation of the Hedgehog pathway in stromal cells. We localized deiodinase expression, assessed changes during injury, and determined how targeted manipulation of Hedgehog signaling in stromal cells impacted hepatic deiodinase expression, TH content, and TH action in rodents. Humans with chronic liver disease were also studied. In healthy liver, hepatocytes strongly expressed D1 and stromal cells weakly expressed D3. During injury, hepatocyte expression of D1 decreased, whereas stromal expression of D3 increased, particularly in myofibroblasts. Conditionally disrupting Hedgehog signaling in myofibroblasts normalized deiodinase expression. Repair-related changes in deiodinases were accompanied by reduced hepatic TH content and TH-regulated gene expression. In patients, this was reflected by increased serum rT3. Moreover, the decreases in the free T3 to rT3 and free T4 to rT3 ratios distinguished advanced from mild fibrosis, even in individuals with similar serum levels of TSH and free T4. In conclusion, the Hedgehog-dependent changes in liver stromal cells drive repair-related changes in hepatic deiodinase expression that promote intrahepatic hypothyroidism, thereby limiting exposure to T3, an important factor for cellular differentiation.

Appropriate dosing of adjuvant radioactive iodine for differentiated thyroid cancer.

PURPOSE OF REVIEW: The incidence of well differentiated thyroid cancer (WDTC) is increasing in the US population and is now a major public health concern. Although surgery is the mainstay of treatment, radioactive iodine (RAI) is routinely used for adjuvant therapy, remnant ablation, and for the treatment of metastatic disease. Despite excellent prognosis and stable mortality rates, the use of RAI is increasing in many low and intermediate risk WDTC patients without clear indication that it changes the outcome. As a result, the current treatment paradigm has shifted towards a risk-stratified approach. RECENT FINDINGS: Although there is widespread acceptance that RAI improves overall and recurrence-free survival in patients with metastatic disease, controversy remains regarding radioactive remnant ablation use in low and intermediate risk patients. Additional studies have shown that reduced doses of RAI can provide similar rates of remnant ablation and adjuvant therapy in low and intermediate risk patients without adversely affecting the recurrence rates and mortality. SUMMARY: Recent studies suggest potential new paradigms in radioactive remnant ablation dosing and indications for use. Risk stratification is important in determining the proper use and dosing of RAI.

Arrestins in bone.

Parathyroid hormone (PTH) is the principle regulator of calcium-phosphorus metabolism and bone turnover. Because of its central role in bone remodeling, recombinant human PTH (i.e., Forteo®; PTH(1-34)) has been developed for the treatment of osteoporosis. PTH(1-34) acts principally through the type I PTH/PTH-related peptide receptor (PTH1R), a classic seven transmembrane G protein-coupled receptor (GPCR). Intermittent treatment with PTH(1-34) promotes osteoblast and osteoclast recruitment through activation of PTH1R with resultant net bone gain. Recent studies have demonstrated that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. ß-Arrestins, in addition to their desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of classic G protein-mediated second messenger-dependent pathways. In vitro, D-Trp(12), Tyr(34)-bPTH(7-34) [bPTH(7-34)], a ß-arrestin-selective biased agonist for the PTH1R, antagonizes G protein signaling but activates arrestin-dependent signaling. In vivo, intermittent administration of bPTH(7-34) to mice induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. While both the conventional PTH1R agonists, PTH(1-34) and bPTH(7-34), stimulate anabolic bone formation in mice, the latter does not induce hypercalcemia nor does it increase markers of bone resorption. This newly recognized ability of ß-arrestins to serve as signal transducers for the PTH1R independent of classic GPCR signaling represents a novel paradigm with therapeutic potential. Exploitation of ß-arrestin-biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis with an improved side effect profile.

Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway.

BACKGROUND: Locally or widely metastatic medullary thyroid carcinoma (MTC) is difficult to treat, and therapeutic options are limited. Recently, kinase inhibitors have shown partial efficacy in this cancer, but there is a continued need for the development of novel therapeutics. Within this context, the Hedgehog (Hh) pathway has been implicated in several types of human tumors, and early clinical trials with Hh antagonists have validated Hh as a novel therapeutic target. For the first time, we evaluated Hh pathway activity in MTC, and examined the effect of Hh pathway perturbation in highly characterized MTC cell lines. METHODS: We examined immunohistochemical expression of the Hh signaling mediators Sonic Hedgehog (Shh) and Glioblastoma (Gli)2 in paraffin-embedded normal versus histologically characterized human MTC tissue. We examined pharmacologic disruption of Hh signaling in vitro using two established MTC cell lines (TT and MZ-CRC-1). Hh signaling was either pharmacologically activated (SAG) or inhibited (GDC-0449) in MTC cell lines; Hh activity was assessed by quantitative real-time polymerase chain reaction, Western blot analysis, and quantification of cellular growth and apoptotic activity. RESULTS: Our data showed increased expression of Hh signaling factors in human MTC compared to normal tissue. In vitro, activation of the Hh pathway resulted in increased expression of key Hh signaling components Smoothened (Smo) and Gli2. Conversely, inhibition of the Hh pathway decreased expression of these genes, leading to significantly reduced cellular growth and increased apoptosis. CONCLUSIONS: Hedgehog signaling components are markedly upregulated in MTC. Hh pathway inhibitors have potential as novel therapeutic options in patients with metastatic and/or surgically unresectable MTC.

Mechanisms of disease progression in NASH: new paradigms.

The incidence of nonalcoholic fatty liver disease is increasing at an astonishing rate in the US population. Although only a small proportion of these patients develop steatohepatitis (NASH), those who do have a greater likelihood of developing end-stage liver disease and complications. Research on liver fibrosis and NASH progression shows that hedgehog (Hh) is reactivated after liver injury to assist in liver repair and regeneration. When the process of tissue repair and regeneration is prolonged or when Hh ligand and related genes are aberrantly regulated and excessive, tissue repair goes awry and NASH progresses to cirrhosis and hepatocellular carcinoma.

Micropapillary thyroid carcinoma and concomitant ectopic thyroid tissue in the adrenal gland: metastasis or metaplasia?

BACKGROUND: Ectopic thyroid tissue is a rare finding but has been reported in many thoracic and abdominal locations. It is usually an incidental pathologic finding after an unrelated surgical intervention. When thyroid tissue is found outside the thyroid bed, it is important to rule out thyroid cancer metastasis. PATIENT FINDINGS: We present a case of a 61-year-old African American woman who was incidentally found to have concomitant ectopic thyroid tissue in the adrenal gland and a papillary thyroid microcarcinoma (PTMC) in the right lobe of the thyroid. SUMMARY: The concurrent finding of ectopic thyroid tissue and PTMC posed the diagnostic dilemma of whether the extrathyroidal tissue was metastasis or metaplasia, with very different treatment implications. Although many of these incidental micropapillary cancers are indolent, some patients do experience local or distant metastasis. Therefore, it is important to delineate which of these microtumors are likely to metastasize. Some tumor markers and gene mutations have been proposed to help differentiate the more benign tumors from the more aggressive tumors, but there is currently no standard method for determination of metastatic potential. CONCLUSIONS: Here we present the seventh known case of ectopic thyroid tissue in the adrenal gland and the first case of concomitant incidental PTMC in the setting of this ectopic tissue finding. Using this case, we discuss the diagnostic and therapeutic challenges faced and propose the use of biomarkers to help determine the metastatic potential of these tumors.

ß-arrestin-biased agonism at the parathyroid hormone receptor uncouples bone formation from bone resorption.

Parathyroid hormone (PTH) is a principle regulator of bone and calcium metabolism and PTH analogs hold great promise as a therapy for metabolic bone diseases such as osteoporosis. PTH acts principally through the type IPTH/PTH-related peptide receptor (PTH1R), a G protein coupled receptor (GPCR). GPCRs are a family of seven transmembrane cell surface receptors that share conserved structural, functional, and regulatory properties. Recent studies demonstrate that the complex metabolic effects induced by PTH1R stimulation are not entirely a consequence of conventional GPCR signaling. ß-arrestins, in addition to their GPCR desensitizing actions, also serve as multifunctional scaffolding proteins linking the PTH1R to signaling molecules independent of the classic G protein coupled second messenger-dependent pathways. In vitro, D-Trp(12),Tyr(34)-bPTH(7-34) (PTH-ßarr), a ß-arrestin selective biased agonist for the PTH1R, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, intermittent administration of, PTH-ßarr to mice, induces anabolic bone formation, completely independent of classic G protein-coupled signaling mechanisms. While both PTH-ßarr and the conventional agonist PTH(1-34) stimulate anabolic bone formation in mice, unlike PTH(1-34), which activates G protein coupling, PTH-ßarr does not induce hypercalcemia or increase markers of bone resorption. This newly recognized ability of ß-arrestins to serve as signal transducers for the PTH1R represents an innovative paradigm of receptor signaling which can be targeted to induce a subset of physiologic responses in bone. Exploitation of ß-arrestin biased agonism may offer therapeutic benefit for the treatment of metabolic bone diseases such as osteoporosis.