Imbalance of Osteoclastogenesis-Regulating Factors in Patients With Celiac Disease

Abstract

Celiac disease is an autoimmune disorder characterized by atrophy of the intestine villi triggered by ingestion of gluten in genetically susceptible individuals. The association between celiac disease and low BMD has been recognized, but the mechanisms of disturbance are poorly understood. We show imbalance of cytokines relevant to bone metabolism in celiac patients' sera and the direct effect of these sera on in vitro bone cell activity.Introduction: Celiac disease is associated with mineral metabolism derangement and low BMD. We investigated whether imbalance of serum factors in celiac patients could affect human bone cell activity in vitro. Materials and Methods:We studied two groups of celiac patients-one on a gluten-free diet and another before the diet-both with decreased bone mass. Patients were investigated for bone turnover markers, and their sera were used for culturing bone cells from healthy donors and evaluate changes in cell activity. Results:The N-terminal telopeptide of procollagen type I and interleukin (IL)-6 were higher than normal in patients not on the gluten-free diet. IL-1␤ and TNF-␣/␤ were normal in all patients. IL-12 was reduced in all patients, whereas IL-18 was reduced only in patients on the diet. The RANKL/Osteoprotegerin (OPG) ratio was increased in patients not on the gluten-free diet. Persistently increased osteoclast numbers were obtained from peripheral blood mononuclear cells of healthy donors on incubation with sera of patients not on the gluten-free diet versus control sera and sera from patients on the diet. In human osteoblasts from healthy individuals, IL-18 was reduced on incubation with sera from all patients, whereas OPG expression was lower when sera from patients not on the diet were used. Proliferation, alkaline phosphatase, and nodule mineralization were increased in osteoblast cultures containing sera from all celiac patients, either on or not on the gluten-free diet. Conclusions: We conclude that bone loss in celiac disease might also be caused by a cytokine imbalance directly affecting osteoclastogenesis and osteoblast activity.

CGRP inhibits osteoprotegerin production in human osteoblast-like cells via cAMP/PKA-dependent pathway

“…Measurements of RANKL in hOB after exposure to CGRP may have given a better insight into the peptide's effect on the cross-talk between bone forming and bone resorbing cells but, as recently reported by others (41), neither the expression nor the secretion of RANKL reached detectable levels thus hampering the possibility of evaluating the cross-talk signal in coculture of human osteoblasts and osteoclasts.…”

Systematic review: the evidence base for long‐term management of coeliac disease

“…Cytokines increase bone turnover and induce cortical bone loss via direct effects on osteoclastogenesis and osteoblast activity and these have been demonstrated in patients with CD. [46][47][48][49][50] Such a mechanism probably underlies the greater reduction in BMD in patients with villous atrophy compared with those with less histologic severity. 51,52 Treatment with GFD and the subsequent reduction in systemic inflammation are associated with improved BMD 53-60 as outlined above.…”

Characterisation of Osteoprotegerin Autoantibodies in Coeliac Disease

“…In coeliac disease up to 20-50% of newly diagnosed patients have reduced bone density, which is usually attributed to associated malabsorption and secondary calcium and vitamin D deficiencies, or to gut inflammation and the release of pro-inflammatory cytokines, though the severity of osteoporosis often bears little relation to the severity of the underlying coeliac disease (9)(10)(11)(12). A gluten-free diet, the only available treatment for coeliac patients, improves bone mass and, consequently, reduces fracture risk, although the co-administration of mineral active drugs may be useful in a subgroup of coeliac disease patients (13).…”