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Interleukin-6 (IL-6) is a potent stimulator of bone resorption which has been demonstrated in a variety of in vivo and in vitro models. We investigated the regulation of IL-6 secretion in primary human osteoblastic cells (HOC) in vitro by cytokines known to play an important role in coupling bone formation to bone resorption. HOC were isolated from healthy adults who underwent selective orthopedic surgery and treated with cytokines released in the bone microenvironment during coupling i.e Interleukin-1beta (IL-1beta), Tumor Necrosis Factor alpha (TNFalpha), Transforming Growth Factor beta1 and 2 (TGFbeta 1 and 2) and Endothelin-1 (ET-1). Furthermore, we determined whether systemically-acting steroid hormones of gonadal and adrenal origin as well as glucocorticoids affect the local regulation of IL-6 secretion in primary HOC. To examine the effects of different steroid hormones on IL-6 production, HOC were exposed to estradiol (E2), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) and dexamethasone (Dexa) with and without a subsequent treatment of the HOC populations with cytokines. We observed that (1) IL-1beta and TNFalpha induced IL-6 in a dose and time-dependent fashion, (2) TGFbeta 1 and 2 enhanced basal and IL-1beta and TNFalpha induced IL-6 expression, (3) ET-1 elicited a dose-dependent stimulatory effect on IL-6 expression. (4) E2, DHT and DHEA alone and in combination with IL-1beta and TNFalpha elicited no reproducible dose-dependent effect on IL-6 production, whereas Dexa inhibited basal and IL-1beta and TNFalpha induced IL-6 expression dose dependently. In conclusion, IL-1beta, TNFalpha, TGFbeta 1 and 2 and ET-1 may participate in the regulation of bone resorption by stimulating IL-6 expression in HOC. Dexa inhibits the constitutive and cytokine stimulated IL-6 expression, whereas there is no in vitro evidence that sex steroids exert a major inhibitory effect on the osteoblastic secretion of IL-6 as demonstrated in a primary human bone cell model.

History and admission findings A 70-year-old man with a 23-year history of recurrent nephrolithiasis was admitted for evaluation of hypercalcaemia (maximal calcium concentration 3.24 mmol/l). Physical examination on admission was unremarkable except for sensory neuropathy in the right foot. Investigations Chest radiogram, subsequent transbronchial lung biopsy, gallium scintigraphy and magnetic resonance imaging (MRI) of the vertebrae indicated generalized sarcoidosis, predominantly affecting the mediastinum, lumbar vertebrae and nerves of the distal limbs. Parathormone level was reduced, while the levels of vitamin D metabolites were normal. Treatment and course Serum calcium level became normal within 2 weeks of starting glucocorticoid treatment. Conclusion Hypercalcaemia can occur in the course of sarcoidosis even in the absence of a elderly increased level of 1,25-dihydroxyvitamin D3. In this case the cause of the hypercalcaemia of a year's duration may have been due to lymphomacrophagocytic infiltration of the bone of several vertebrae as demonstrated by MRI of the vertebral columns but not by conventional radiography. In this case an increase in cytokine secretion by macrophages may have played an important role in addition to the level of 1,25-dihydroxyvitamin D3 at the upper limit of normal that, in view of the renal failure, could only have been caused by extrarenal production. Cytokines (e.g. interleukin-1 beta and tumour necrosis factor alpha) secreted by activated macrophages are among the most powerful stimulators of bone reabsorption.