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Front. Immunol. | doi: 10.3389/fimmu.2019.02666

Commentary: Circulatory pattern of cytokines, adipokines and bone markers in postmenopausal women with low BMD.

  • 1Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali, Universita' degli Studi di Messina, Italy
  • 2Department of Clinical and Experimental Medicine, University of Messina, Italy

Osteoporosis, one of the most important conditions associated with aging, is characterized by low bone mass and micro-architectural bone tissue deterioration, due to bone resorption and bone formation imbalance (1,2). Immune system contributes to postmenopausal osteoporosis through pro-inflammatory cytokines modulation of osteoblast and osteoclast activity (3–6). It has been also suggested that adipose tissue influences regulation of bone metabolism contributing to osteoporosis pathophysiology, thanks to its independent endocrine and paracrine activity associated with adipokines production (7,8).
We have read with great interest the article by Azizieh et al., 2019 (8), aimed at measuring circulatory levels of several cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, TNF-α, IFN-γ, TGF-β), adipokines, bone turnover markers density and estradiol level in postmenopausal women with normal and low bone mineral density (BMD). Results showed that circulatory cytokine levels were comparable in women with low or normal BMD. Women with low BMD, showed a statistically significant higher median circulatory levels of adipokines than women with normal BMD. Moreover, while C-terminal cross-linking telopeptide of type I collagen (CTX) levels were not different between the two groups, procollagen type I N propeptide (PINP), PINP/CTX ratio and estradiol levels were significantly lower in women with low BMD. Adiponectin, PINP, PINP/CTX ratio and estradiol levels correlated significantly with BMD of the hip and spine (8).
We congratulate the authors for remarkable study and we agree that results indicate the possible role of the considered cytokines, adipokines and bone turnover markers in the pathogenesis of postmenopausal osteoporosis. Here we focus on the role of IL-31/IL-33 axis.
Interleukin-33 (IL-33) belongs to IL-1 cytokine family, it is mainly expressed in stromal cells, and upregulated following pro-inflammatory stimulation (9).
IL-33, described as Th2 cytokine inducer, is considered a traditional cytokine, an “alarmin” and a nuclear factor controlling gene transcription (10). IL-33 has powerful effects on many cell types such as ILC2s (type 2 innate lymphoid cells), mast cells, eosinophils, and Th2 lymphocytes, in particular, IL-33 plays a major role in ILC2 recruitment. IL-33 activates ILC2s via NF‐κB and MAPK signaling pathways, causing enhancement of production of cytokines, chemokines and peptides (11-15). The responsiveness to these cytokines depends on resident tissues and species, and co‐stimulatory cytokines are required for activation (16).
It has been also demonstrated that IL-33 increases its expression after cell death, resulting in the induction of other cytokines including IL-31 (10).
Interleukin-31 (IL-31), belongs to gp130/IL-6 cytokine family expressed by activated memory CD45RO+ T lymphocytes skewed toward a Th2 phenotype (17-19). Scientific evidence shows a biological role for IL-31 in immunity and inflammation (17,18). Several cytokines and transcription factors are involved in the development of osteoporosis, and some of them are regulated by IL-31 (18-21). Engagement of the receptor complex results in activation of Janus kinase and different signaling molecules, including signal transducers and activators of transcription factors, Akt, NF-κB (12,13,18), MAPK (17,18) and PI3K signaling pathways (19). These pathways are involved both in bone remodeling and inflammation (20,21).
In our previous studies, based on IL-31 and IL-33 role in inflammation and bone remodeling (22-24) we evaluated, their involvement in postmenopausal osteoporosis. Measurements of serum IL-31 and IL-33 were performed both in women with osteoporosis and healthy women as controls. Osteoporosis was evaluated by BMD measurement expressed as T-score (23).
Our results showed a statistically significant increase of IL-31 serum levels in postmenopausal women with decreased BMD, suggesting a role of IL-31 in osteoporosis. Serum IL-31 levels is not related with the severity of osteoporosis, as indicated by BMD values and/or the presence of fractures (23).
Serum IL-33 levels were significantly lower in postmenopausal osteoporotic patients than non osteoporotic patients and a correlation between IL-33 and PTH serum levels was also observed (24).
Though the direct effect of IL-33 on osteoclast function or bone resorption is not clear, our results showing a negative correlation between IL-33 and CTX seem to confirm the inhibition of osteoclast differentiation mediated by IL-33 (24).
The lower levels of IL-33 found in osteoporotic patients agree with several experimental observations showing inhibition of osteoclast differentiation by IL-33 (25-27). It is known that IL-33 inhibits RANKL-dependent osteoclast formation, protecting from inflammatory bone loss (28,29). Furthermore, IL-33 inhibits osteoclast differentiation by inducing antiosteoclastogenic cytokines such as IL-10, IL-4 and IFN-γ and granulocyte-macrophage colony-stimulating factor, skewing osteoclast precursors differentiation to alternatively activated macrophage and dendritic cells (25). It has been also suggested a RANKL-like action of IL-33 in human osteoclast formation (30). IL-33 pro-resorption effects on bone is weak and highly variable, compared to the strong effect of RANKL, with some types of osteoclast progenitors that differentiate into functional resorbing cells consequent to IL-33 stimulation and other osteoclast progenitor-containing unresponsive populations (31).
IL-31 serum levels increase in aged osteoporotic patients, suggesting a link between bone resorption and cytokine overexpression, that could enhance bone resorption through chemokines and induction of proinflammatory osteoclastogenic cytokines, leading to osteoclast precursors recruitment, differentiation and activation. Our results suggest a key role of IL-31 in senile osteoporosis but the exact mechanism of action remains unknown. A clear understanding of IL-31 involvement in bone resorption immunopathology can provide more effective strategies for the treatment of senile osteoporosis.
Our data suggest the existence of an IL-31 and IL-33 correlation axis. This is in accordance with other authors that showed an involvement of IL-33/ST2 axis in the progression of several inflammatory diseases, influencing the generation of Th17, producing IL-31 (32,33). High serum levelof IL-31 and IL-33 have been also reported in people with inflammatory and autoimmune diseases (33,34). IL-31 and IL-33 are linked to each other, induction of one citokyne by the other is correlated with disease severity, inflammation and harmful processes. Data suggest that IL-33/ST2 axis activation can be considered a biomarker of both Th2/IL-31 and Th17 immune response (10,34).
Our results can contribute to better understand the mechanisms at the basis of the immune system capacity to mount osteoclastogenic immune reactions through inflammatory responses crucial in senile osteoporosis. Moreover, IL-33 could be considered an important bone-protecting cytokine becoming a target in the prevention and therapy of postmenopausal osteoporosis.

Keywords: IL-31, IL-33, IL31/33 axis, Osteoporosis, Post-menopausal osteoporosis, Inflammation

Received: 04 Jul 2019; Accepted: 28 Oct 2019.

Copyright: © 2019 Mannucci, Calapai and Gangemi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Carmen Mannucci, Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali, Universita' degli Studi di Messina, Messina, Italy,