AUTHOR=Gomes Ana Cordeiro , Sousa Daniela Monteiro , Oliveira Tiago Carvalho , Fonseca Óscar , Pinto Ricardo J. , Silvério Diogo , Fernandes Ana Isabel , Moreira Ana C. , Silva Tânia , Teles Maria José , Pereira Luísa , Saraiva Margarida , Lamghari Meriem , Gomes Maria Salomé TITLE=Serum amyloid A proteins reduce bone mass during mycobacterial infections JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1168607 DOI=10.3389/fimmu.2023.1168607 ISSN=1664-3224 ABSTRACT=Introduction

Osteopenia has been associated to several inflammatory conditions, including mycobacterial infections. How mycobacteria cause bone loss remains elusive, but direct bone infection may not be required.

Methods

Genetically engineered mice and morphometric, transcriptomic, and functional analyses were used. Additionally, inflammatory mediators and bone turnover markers were measured in the serum of healthy controls, individuals with latent tuberculosis and patients with active tuberculosis.

Results and discussion

We found that infection with Mycobacterium avium impacts bone turnover by decreasing bone formation and increasing bone resorption, in an IFNγ- and TNFα-dependent manner. IFNγ produced during infection enhanced macrophage TNFα secretion, which in turn increased the production of serum amyloid A (SAA) 3. Saa3 expression was upregulated in the bone of both M. avium- and M. tuberculosis-infected mice and SAA1 and 2 proteins (that share a high homology with murine SAA3 protein) were increased in the serum of patients with active tuberculosis. Furthermore, the increased SAA levels seen in active tuberculosis patients correlated with altered serum bone turnover markers. Additionally, human SAA proteins impaired bone matrix deposition and increased osteoclastogenesis in vitro. Overall, we report a novel crosstalk between the cytokine-SAA network operating in macrophages and bone homeostasis. These findings contribute to a better understanding of the mechanisms of bone loss during infection and open the way to pharmacological intervention. Additionally, our data and disclose SAA proteins as potential biomarkers of bone loss during infection by mycobacteria.