ArticleThe Journal of biological chemistry2014
Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 70 citations in OpenAlex.
- Sequential activation of the AKT pathway in human osteoblasts treated with Oscarvit: a bioactive product with positive effect both on skeletal pain and mineralization in osteoblasts.BMC musculoskeletal disorders · 2017Trial
- Siglec-15 as a potential molecule involved in osteoclast differentiation and bone metabolism.Heliyon · 2024Review
- Regulation of Glycosylation in Bone Metabolism.International journal of molecular sciences · 2024Review
- Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Siglec15 in blood system diseases: from bench to bedside.Frontiers in immunology · 2024Review
- Expression of SIGLEC15 correlates with tumor immune infiltration, molecular subtypes, and breast cancer progression.PloS one · 2024Article
- Anti-Siglec-15 Antibody Prevents Marked Bone Loss after Acute Spinal Cord Injury-Induced Immobilization in Rats.JBMR plus · 2023Article
- Siglec-15 Promotes Evasion of Adaptive Immunity in B-cell Acute Lymphoblastic Leukemia.Cancer research communications · 2023Article
- The new progress in cancer immunotherapy.Clinical and experimental medicine · 2023Review
- Discovery, classification, evolution and diversity of Siglecs.Molecular aspects of medicine · 2023Review
- Activation of immune signals during organ transplantation.Signal transduction and targeted therapy · 2023Review
- Significance of Siglec-15 expression in colorectal cancer: association with advanced disease stage and fewer tumor-infiltrating lymphocytes.The journal of pathology. Clinical research · 2023Article
- Tumor stroma Siglec15 expression is a poor prognosis predictor in colon adenocarcinoma.Journal of Cancer · 2023Article
- Dynamic change in Siglec-15 expression in peritumoral macrophages confers an immunosuppressive microenvironment and poor outcome in glioma.Frontiers in immunology · 2023Article
- Myeloid checkpoints for cancer immunotherapy.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2022Article
- Sialylation of TLR2 initiates osteoclast fusion.Bone research · 2022Article
- Long Noncoding RNA TUG1 Inhibits Tumor Progression through Regulating Siglec-15-Related Anti-Immune Activity in Hepatocellular Carcinoma.Journal of immunology research · 2022Article
- High affinity monoclonal antibody targeting Siglec-15 for cancer immunotherapy.Journal of clinical and translational research · 2021Article
- An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAPBone research · 2021Article
- The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans.Nature reviews. Drug discovery · 2021Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 up-regulated during osteoclast differentiation induced by the cytokine receptor activator of NF-κB ligand (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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.