The role of Siglec-9/ Siglec-E in osteoclastogenesis
Final Report Abstract
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are transmembrane receptors that recognize sialic-acid containing structures on glykoproteins and glycolipids. Siglec-9 and its murine homolog Siglec-E belong to the CD33-Siglec family and are mainly expressed by myeloid cells. Several studies have shown that Siglec-9/-E affect the migration and cytokine expression of neutrophil granulocytes and macrophages. Osteoclasts are the only bone resorbing cells of the body. They are multinucleated giant cells that develop by cell fusion from macrophage-like precursors. It was not known if Siglec-9/- E affect osteoclasts and we investigated this topic in this project. Siglec-E deficient mice displayed a lowered bone mass compared to their wild type littermates. Interestingly, the number of bone- resorbing osteoclasts and bone-forming osteoblasts was unchanged. From these results, we hypothesized that not the osteoclast differentiation, but activation is diminished by Siglec-E. This hypothesis was confirmed by murine osteoclast assays. In addition, we found in human osteoclast assays that silencing Siglec-9 with blocking antibodies resulted into an increased osteoclast activity and thereby bone resorption. In the second part of our project, we investigated the effects of Siglec- 9/-E on diseases with inflammatory bone loss, such as rheumatoid arthritis. It is known that Siglec-9 dampens neutrophil granulocytes and thereby inflammation. Although we did not find a difference in the Siglec-9 expression on neutrophil granulocytes between healthy persons and patients with rheumatoid arthritis, we saw a correlation between higher Siglec-9 expression levels and lower disease activity in the patients. This finding was confirmed in a murine model of inflammatory arthritis, that showed no change in the initiation of disease, but higher disease scores in the resolution phase in Siglec-E deficient mice. Together, our data from this project show that Siglec-9/-E protects against bone loss in general and against inflammatory reactions in rheumatoid Arthritis. These findings make Siglec-9/-E an interesting target for future therapeutic strategies.
Publications
- The Role of Autoantibodies in Bone Metabolism and Bone Loss. Calcif Tissue Int. 2018 May;102(5):522-532
Hauser B, Harre U
(See online at https://doi.org/10.1007/s00223-017-0370-4) - Generation and Analysis of Human and Murine Osteoclasts. Curr Protoc Immunol. 2019 Jun;125(1):e74
Steffen U, Andes FT, Schett G
(See online at https://doi.org/10.1002/cpim.74) - How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis. Front Immunol. 2019 Jul 3;10:1483
Steffen U, Schett G, Bozec A
(See online at https://doi.org/10.3389/fimmu.2019.01483)
