Continuous rhPTH (1-34) treatment in chronic hypoparathyroidism.

SUMMARY: Standard treatment of hypoparathyroidism consists of supplementation of calcium and vitamin D analogues, which does not fully restore calcium homeostasis. In some patients, hypoparathyroidism is refractory to standard treatment with persistent low serum calcium levels and associated clinical complications. Here, we report on three patients (58-year-old male, 52-year-old female, and 48-year-old female) suffering from severe treatment-refractory postsurgical hypoparathyroidism. Two patients had persistent hypocalcemia despite oral treatment with up to 4 µg calcitriol and up to 4 g calcium per day necessitating additional i.v. administration of calcium gluconate 2-3 times per week, whereas the third patient presented with high frequencies of hypocalcemic and treatment-associated hypercalcemic episodes. S.c. administration of rhPTH (1-34) twice daily (40 µg/day) or rhPTH (1-84) (100 µg/day) only temporarily increased serum calcium levels but did not lead to long-term stabilization. In all three cases, treatment with rhPTH (1-34) as continuous s.c. infusion via insulin pump was initiated. Normalization of serum calcium and serum phosphate levels was observed within 1 week at daily 1-34 parathyroid hormone doses of 15 µg to 29.4 µg. Oral vitamin D and calcium treatment could be stopped or reduced and regular i.v. calcium administration was no more necessary. Ongoing efficacy of this treatment has been documented for up to 7 years so far. Therefore, we conclude that hypoparathyroidism that is refractory to both conventional treatment and s.c. parathyroid hormone (single or twice daily) may be successfully treated with continuous parathyroid hormone administration via insulin pump. LEARNING POINTS: Standard treatment of hypoparathyroidism still consists of administration of calcium and active vitamin D. Very few patients with hypoparathyroidism also do not respond sufficiently to standard treatment or administration of s.c. parathyroid hormone once or twice daily. In those cases, continuous s.c. administration of parathyroid hormone via insulin pump may represent a successful treatment alternative.

Oncogenic deletion mutants of gp130 signal from intracellular compartments.

Interleukin 6 (IL-6) and, hence, activation of the IL-6 receptor signalling subunit glycoprotein 130 (gp130; also known as interleukin-6 receptor subunit ß, IL6ST), has been linked to inflammation and tumour formation. Recently, deletion mutations in gp130 have been identified in inflammatory hepatocellular adenoma. The mutations clustered around one IL-6-binding epitope and rendered gp130 constitutively active in a ligand-independent manner. Here, we show that gp130 deletion mutants, but not wild-type gp130, localise predominantly to intracellular compartments, notably the endoplasmic reticulum (ER) and early endosomes. One of the most frequent mutants, gp130 Y186-Y190del (ΔYY) is retained in the ER quality control system because of its association with the chaperone calnexin. Furthermore, we can show that gp130 ΔYY induces downstream signalling from both ER and endosomes, and that both signals contribute to ligand-independent cell proliferation. We also demonstrate that the endosomal localisation of gp130 ΔYY is crucial for fully fledged STAT3 activation. Therefore, aberrant signalling from intracellular compartments might explain the tumorigenic potential of naturally occurring somatic mutations of gp130.

gp130 activation is regulated by D2-D3 interdomain connectivity.

Activation of the IL-6 (interleukin 6) receptor subunit gp130 (glycoprotein 130) has been linked to the formation of complexes with IL-6 and the IL-6 receptor, as well as to gp130 dimerization. However, it has been shown that gp130 is present as a pre-formed dimer, indicating that its activation is not solely dependent on dimerization. Therefore the detailed mechanism of gp130 activation still remains to be deciphered. Recently, deletion mutations of gp130 have been found in inflammatory hepatocellular adenoma. The mutations clustered around one IL-6-binding epitope of gp130 and resulted in a ligand-independent constitutively active gp130. We therefore hypothesized that conformational changes of this particular IL-6-binding epitope precedes gp130 activation. Using a rational structure-based approach we identified for the first time amino acids critical for gp130 activation. We can show that gp130 D2-D3 interdomain connectivity by hydrophobic residues stabilizes inactive gp130 conformation. Conformational destabilization of the EF loop present in domain D2 and disruption of D2-D3 hydrophobic interactions resulted in ligand-independent gp130 activation. Furthermore we show that the N-terminal amino acid residues of domain D1 participate in the activation of the gp130 deletion mutants. Taken together we present novel insights into the molecular basis of the activation of a cytokine receptor signalling subunit.