Mechanism and Function of Monoclonal Antibodies Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption
ABSTRACT The use of monoclonal antibodies to target functionally important cell-surface proteins on bone-resorbing osteoclasts represents a promising approach for treatment of cancer-associated bone loss and other skeletal pathologies. Previously, we identified Siglec-15, a little-studied sialic acid-binding receptor, as a candidate target that is highly upregulated during osteoclast differentiation induced by the cytokine RANKL. In this report, we confirm that Siglec-15 is localized to the plasma membrane where it can be targeted by monoclonal antibodies to inhibit differentiation of functional osteoclasts in vitro. Furthermore, we found that treatment of mice with these antibodies led to a marked increase in bone mineral density, consistent with inhibition of osteoclast activity. Interestingly, osteoblast numbers were maintained despite the anti-resorptive activity. At the molecular level, Siglec-15 interacts with the adapter protein DAP12 and can induce Akt activation when clustered on the osteoclast cell surface, which likely represents its normal signaling function. Importantly, we discovered that monoclonal antibodies induce rapid internalization, lysosomal targeting and degradation of Siglec-15 by inducing receptor dimerization. This study defines a key regulatory node that controls osteoclast differentiation and activity downstream of RANKL and supports further development of Siglec-15 antibodies as a novel class of bone loss therapeutics.
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ABSTRACT: All mammalian cells display a diverse array of glycan structures that differ from those that are found on microbial pathogens. Siglecs are a family of sialic acid-binding immunoglobulin-like receptors that participate in the discrimination between self and non-self, and that regulate the function of cells in the innate and adaptive immune systems through the recognition of their glycan ligands. In this Review, we describe the recent advances in our understanding of the roles of Siglecs in the regulation of immune cell function in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer.Nature reviews. Immunology 09/2014; 14(10). DOI:10.1038/nri3737 · 33.84 Impact Factor
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ABSTRACT: We investigated whether blockade of Siglec-15 is effective for preventing estrogen deficiency-induced bone loss in a mouse ovariectomy model.•Siglec-15-/- mice showed resistance to estrogen deficiency-induced bone loss.•Osteoclast development was impaired in ovariectomized Siglec-15-/- mice.•The TNF-α mediated induction of TRAP-positive multinucleated cells was impaired in Siglec-15-/- cells.Bone 11/2014; 71. DOI:10.1016/j.bone.2014.10.027 · 4.46 Impact Factor