title: Role of the interleukin-6/interleukin-6 soluble receptor cytokine system in mediating increased skeletal sensitivity to parathyroid hormone in perimenopausal women.
abstract: We have observed a strong correlation between circulating levels of both interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) and rates of bone turnover in patients with primary hyperparathyroidism. Furthermore, we have found that serum levels of IL-6sR predict rates of bone loss in postmenopausal women with this disease. Estrogen modulates parathyroid hormone (PTH)-induced increases in serum IL-6/IL-6sR, such that, in the estrogen-deficient state, there is an exaggerated release of these cytokines. We therefore propose that the perimenopausal period represents a time when skeletal sensitivity to the resorbing actions of PTH increases because of augmented release of IL-6 and IL-6sR. To test this hypothesis, we retrospectively examined data from 91 women with primary hyperparathyroidism who were seen over the last 5 years at our institution. Women were categorized, based on their age, as premenopausal (n = 20, 41 +/- 2 years), perimenopausal (n = 17, 54 +/- 1 years), or postmenopausal (n = 54, 64 +/- 1 years). Despite having similar mean values for PTH, perimenopausal women had a mean serum IL-6 value that was significantly higher than that in the premenopausal group (13 +/- 2 vs. 8 +/- 2 pg/ml; p = 0.03). This difference in cytokine profile was mirrored by higher mean values for urine N telopeptides of type I collagen (NTX) in the perimenopausal group compared with premenopausal women (114 +/- 9 vs. 80 +/- 11 nM bone collagen equivalents (BCE)/mM creatinine, p = 0.01). Of the three groups of patients, values for IL-6 and urine NTX were highest in the postmenopausal group. We conclude that the perimenopausal period may be a time of increased risk for the skeletal complications of hyperparathyroidism. This is because of increased skeletal sensitivity to the resorbing actions of PTH, mediated in part, by the IL-6/IL-6sR cytokine system.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Insogna
authors.forename: Maryann
authors.initials: M
authors.lastname: Mitnick
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pascarella
authors.forename: Inaam
authors.initials: I
authors.lastname: Nakchbandi
authors.forename: Andrew
authors.initials: A
authors.lastname: Grey
authors.forename: Urszula
authors.initials: U
authors.lastname: Masiukiewicz
mesh_terms: D000328:Adult; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D003094:Collagen / Q000652:urine; D024042:Collagen Type I; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004967:Estrogens / Q000172:deficiency / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006961:Hyperparathyroidism / Q000150:complications / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000502:physiology*; D008593:Menopause / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000150:complications / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D010455:Peptides / Q000652:urine; D017698:Postmenopause / Q000378:metabolism; D011237:Predictive Value of Tests; D017697:Premenopause / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012189:Retrospective Studies
chemical_list: D024042:Collagen Type I; D016207:Cytokines; D004967:Estrogens; D015850:Interleukin-6; D010281:Parathyroid Hormone; D010455:Peptides; D019947:Receptors, Interleukin-6; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen