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Objectives: Epidemiological evidence supports a link between atherosclerosis and osteoporosis. These conditions might share common pathophysiological mechanisms, with inflammation being one of the hypotheses.Apolipoprotein E deficient mice (ApoE-/-) develop atherosclerotic lesions spontaneously, further aggravated by a high-fat diet. Their bone remodelling is also disturbed. We hypothesised that a proinflammatory state could be a common contributive factor for vessel and bone disturbances observed in this animal model., Methods: We evaluated vessels and bones of ApoE-/- and control C57BL/6 (B6) female mice fed a high-fat diet in five time-points (8, 16, 20, 24 and 28 weeks of age) and quantified the development of atherosclerotic lesions, analysed gene expression of inflammatory and bone remodelling proteins (IL-1β, IL-6, IL-17A, TNF, RANKL, and OPG), measured serum bone turnover markers (P1NP and CTX-I), performed bone (L3-L4 vertebras) histomorphometric analysis and evaluated biomechanical properties of bones., Results: We compared the outcomes of B6 and ApoE-/- groups at each time-point and, within each group, over time. Atherosclerotic lesions developed as previously described for ApoE-/- mice, but no significant differences were found in bone histomorphometry or biomechanical properties between ApoE-/- and B6 mice. Also, gene expression (either in bones or aortas) and serum biomarkers were similar in both groups. When considering over time evaluations we found that bone histomorphometry changes were similar between ApoE-/- and B6 mice, but CTX-I/P1NP ratio was significantly increased (meaning higher resorption than bone formation) in ApoE-/- as compared to B6 mice., Conclusions: Our study suggests that inflammation is not the principal driver for atherosclerosis progression and bone disturbances in this animal model.

Background and Aims: Atherosclerosis and osteoporosis share common risk factors, as well as inflammatory mechanisms. Our aim was to understand how atherosclerotic lesions are related with disturbances in bone. Methods: Gene expression of pro-inflammatory and bone metabolism related proteins ( IL-1 β , IL-6, IL-17A, TNF, RANKL, OPG, COL1, CTSK, OCL, TRAP, CBFA1, DKK1, SOST, ADIPOQ , and ADIPOR1 ) were analyzed in arteries and bones from 45 deceased donors and adipose tissue was used as control. Additionally, in 139 patients with advanced atherosclerosis submitted to carotid endarterectomy we compared calcium content (Alizarin red) and plaque inflammatory scores (CD3 + , CD68 + , and adiponectin) of patients with normal bone mineral density (BMD) with those with low BMD and explored the associations between gene expression in atherosclerotic plaques and BMD. Serum levels of pro-inflammatory and bone related proteins were measured both in donors and patients. Associations were investigated by the Pearson or Spearman correlation tests, and multivariate regression analyzes were performed when justified. Results: Gene expression of bone remodeling and pro-inflammatory proteins correlated positively in bone and aorta, independently of age and sex of donors, but not in adipose tissue. The expression of bone formation genes was significantly higher in atheroma plaques from endarterectomized patients with normal vs. low BMD as well as inflammatory CD68 + scores, regardless of patients' age and sex, but not of body mass index. No relationship was observed between serum levels and gene expression levels of pro-inflammatory or bone remodeling proteins. Conclusions: Our results suggest that the relationship between bones and vessels in the context of atherosclerotic disease and osteoporosis may rely on the intrinsic connection between the tissues involved, independently of disease stage. Serum measurements of pro-inflammatory and bone-remodeling proteins do not accurately translate tissue pathologic processes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carmona-Fernandes, Barreira, Leonardo, Casimiro, Castro, Santos, Fernandes, Cortes-Figueiredo, Gonçalves, Cruz, Fernandes, Ivo, Pedro, Canhão, Fonseca and Santos.)