Expression of Ca_v1.3 calcium channel in the human and mouse colon: posttranscriptional inhibition by IFNγ

Abstract

It has been hypothesized that apically expressed L-type Ca channel Ca1.3 (encoded by CACNA1D gene) contributes toward an alternative TRPV6-independent route of intestinal epithelial Ca absorption, especially during digestion when high luminal concentration of Ca and other nutrients limit TRPV6 contribution. We and others have implicated altered expression and activity of key mediators of intestinal and renal Ca (re)absorption as contributors to negative systemic Ca balance and bone loss in intestinal inflammation. Here, we investigated the effects of experimental colitis and related inflammatory mediators on colonic Ca1.3 expression. We confirmed Ca1.3 expression within the segments of the mouse and human gastrointestinal tract. Consistent with available microarray data (GEO database) from inflammatory bowel disease (IBD) patients, mouse colonic expression of Ca1.3 was significantly reduced in trinitrobenzene sulfonic acid (TNBS) colitis. In vitro, IFNγ most potently reduced Ca1.3 expression. We reproduced these findings in vivo with wild-type and Stat1 mice injected with IFNγ. The observed effect in Stat1 suggested a noncanonical transcriptional repression or a posttranscriptional mechanism. In support of the latter, we observed no effect on the cloned Ca1.3 gene promoter activity and accelerated Ca1.3 mRNA decay rate in IFNγ-treated HCT116 cells. While the relative contribution of Ca1.3 to intestinal Ca absorption and its value as a therapeutic target remain to be established, we postulate that Ca1.3 downregulation in IBD may contribute to the negative systemic Ca balance, to increased bone resorption, and to reduced bone mineral density in IBD patients.

Intestinal Inflammation Promotes MDL-1+ Osteoclast Precursor Expansion to Trigger Osteoclastogenesis and Bone Loss

“…Therefore, these data do not exclude additional complementary mechanisms of IBD-associated bone loss that occur through nutritional deficits or altered osteoblast function, which have been highlighted in previous studies. 31 , 32 , 33 , 59 , 60 , 61 , 62 We did observe bone loss in colitis models that were not associated with significant weight loss, which is consistent with previous reports and may point to mechanisms that are independent of nutritional status. 33 Future studies should address the relative contributions of OCPs, nutritional status, and osteoblast function in contributing to bone loss during intestinal inflammation.…”

The effects and predictive value of calcium and magnesium concentrations on nutritional improvement, inflammatory response and diagnosis in patients with Crohn's disease

“…5 Our study found significantly lower concentrations of calcium in the CD patients compared with the control group, especially in patients in the active phase, with 60.8% of overall CD patients and 75.7% of those in the active phase being hypocalcaemia. In particular, the negative calcium balance behind hypocalcaemia has been found to be associated with a higher incidence of osteoporosis, together with fractures, in patients with CD, 17,18 thus affecting their long-term prognosis. Above all, a major cause of the negative calcium balance was insufficient supplementation of dietary calcium.…”

Calcium physiology, metabolism and supplementation: a glance at patients with ankylosing spondylitis

“…Both intestinal subclinical inflammation and dys biosis may affect the absorption of calcium and other nutrients. Experiments on human cells and experimen tal models of IBD showed that interferongamma (IFNγ) can downregulate the expression in colon of Ltype calcium channels [19], and that inflammation may over all repress the expression of TRPV6, calbindin D9K and other calcium transporters in the duodenal epithelium [20], thus reducing the amount of absorbable calcium.…”

“…Additionally, it has been estimated that onethird of IBD subjects have an inadequate calcium intake due to dietary habits [23]. Notably, supplementation with calcium and vitamin D may be insufficient to prevent osteo porosis in IBD patients, and this may be due to the downregulation of calcium transporters in inflamed gut mucosa as reported in preclinical studies [19,20].…”