Endocannabinoid System and Bone Loss in Celiac Disease

See “The Role of Cannabinoid Receptor Type 2 in the Bone Loss Associated With Pediatric Celiac Disease” by Tortora et al on page 633. Celiac disease (CD) is an immune-mediated disorder characterized by a high prevalence of bone loss, which encompasses at least 2 main pathophysiological mechanisms, malabsorption and chronic inflammation (1–2). The first one is driven by the presence of intestinal lesions causing calcium malabsorption and leading to a network of compensatory events hierarchically aimed to keep a normal calcium level. Accordingly, the prompt release of parathyroid hormone increases calcium release from bone, considered in such a phase a useful calcium storage system, and allows the conversion of 25-vitamin D to 1,25-vitamin D to increase the absorption of calcium at intestinal level. Unfortunately, the presence of negligible amounts of calbindin in the flattened intestinal mucosa makes ineffective this compensatory branch (1) and makes bone the main actor supporting the burden of the compensatory pathway. Intestinal lesions are the result of a gluten-directed, immune-mediated reaction in the context of a chronic inflammation: in untreated CD, elevated serum levels of pro-inflammatory cytokines (IL-1, IL-6, TNF-alfa) and reduced serum levels of inhibitory cytokines (IL-12 and IL-18) were shown and these alterations improve but not normalize after gluten-free diet (GFD) (3,4). This cytokine pattern is associated to an increased bone turnover that in CD patients probably begins before a reduction of bone mineral density (BMD) is evident. Accordingly, this pathway should be considered a pivotal mechanism in CD patients and could explain bone derangement, in particular, in minor CD patients with paucisymptomatic disease, without malabsorption. In treated CD, even if alterations of intestinal absorption are reverted and all nutritional deficiencies are compensated during a rigorous gluten-free diet, subtle alterations of villous architecture persist: finger-like villous morphology is rarely detected as most of the patients show aspects of ridges and leaves. This persistent morphological abnormality has received little attention and it has never represented a target for more aggressive treatment in CD, probably because of the efficacy of small bowel in nutrient absorption after an appropriate period of rigorous gluten-free diet, despite its presence. It is, however, conceivable that the diet contamination with gluten traces is the main pathophysiological mechanism for this abnormality and, consequently, we should infer that the persistence of small bowel inflammation could be responsible for the difficult recovery of bone loss in adult CD (2). In the article from Tortora et al (5), in comparison with control osteoclasts, osteoclasts derived from children with untreated CD showed a significant reduction of CB2 receptor expression associated to a significant increase of osteoclast biomarkers proteins, tartrate-resistant acid phosphatase (TRAP) and cathepsin K. The pharmacological modulation of CB2 receptor with an agonist or an antagonist produced, respectively, a reduced and an increased expression of these markers. These results might suggest a predictive role of bone derangement for CB2 expression and could open the way for a pharmacological application of the endocannabinoid system in the treatment of metabolic bone disease. The determination in vitro of CB2 expression on osteoclasts, however, derived from CD patients as a marker of bone derangement unlikely will represent a useful test in clinical practice: this is a troublesome method, not broadly available, and could become just the charm for a selected group of high-level labs. On the contrary, the serum detection of product of the activity of cathepsin K could be a good compromise, offering the chance for a possible wide diffusion. The reduced CB2 expression on osteoclasts conflicts with the upregulation of CB2 on immune cells in the small bowel mucosa of both children and adults (6,7). Both alterations proved to be sensitive to GFD, however, a 1-year period of diet normalizes CB2 expression in the small intestine, whereas a significant improvement but not normalization is achieved on osteoclasts. If it is possible that a longer period of GFD should be considered to reach this normalization, we have to hypothesize a different regulation of CB2 expression in bone and small bowel. Accordingly, before considering CB2 as a possible target for a new treatment, this discrepancy should be explained in details. The importance of the results from Tortora and co-workers, first of all, relies on pathophysiological grounds. The results were obtained in children with an age range 5 ± 3 years, that is, a clinical setting characterized by increased metabolic needs, requested by growth. This peculiar model enhances the abnormalities at bone level and allows for useful pathophysiological hypothesis. In contrast to adult CD patients diagnosed in adulthood, adult patients on GFD from childhood, normalize BMD without the need of pharmacological treatments (8); this observation strongly suggests that all results on CD-related metabolic bone disorder in children should be preliminary confirmed in adults. Starting from the demonstration of the increased prevalence of a CB2 functional variant in patients with CD (6), now associated with a reduction of CB2 activity in untreated patients reverted by pharmacological stimulation of CD-derived osteoclasts (5), the attention should be immediately directed towards the regulatory pathways of the endocannabinoid system and its connections with other bone pro-resorptive agents. The ability of CB2 to induce the transition of macrophage phenotype polarization from the classical M1 to an alternative M2, reducing bone aggression by inflammatory response, reducing pro-inflammatory and increasing anti-inflammatory cytokines (9) may represent an important mechanism of action of the endocannabinoid pathway. In definitive, the interrelations among pro-inflammatory and anti-inflammatory pathways should be an important topic for the research agenda of the next future to gain new insights in the pathophysiology of bone loss in CD.

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