{"gene":"OMD","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":1998,"finding":"Osteoadherin (OMD/OSAD) was isolated from bovine bone as a keratan sulfate proteoglycan and shown to bind hydroxyapatite and promote osteoblast attachment in vitro as efficiently as fibronectin; cell binding was shown to be mediated specifically by integrin αvβ3, isolated by osteoadherin affinity chromatography of surface-iodinated osteoblast extracts.","method":"Protein purification, affinity chromatography, integrin isolation, in vitro cell attachment assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (purification, affinity chromatography, cell attachment assay) in a single foundational study with 105 citations","pmids":["9566981"],"is_preprint":false},{"year":1998,"finding":"The primary structure of osteoadherin was determined, revealing 11 leucine-rich repeats, a highly acidic C-terminal domain, six N-linked glycosylation sites, and keratan sulfate chains; mRNA expression was restricted to bone (osteoblasts), confirmed by Northern blot and in situ hybridization.","method":"cDNA cloning, sequencing, Northern blot, in situ hybridization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — full primary structure determination with multiple validation methods, 83 citations","pmids":["9642227"],"is_preprint":false},{"year":2009,"finding":"The tyrosine sulfate-rich N-terminal domain of osteoadherin binds heparin-binding proteins including bFGF-2, thrombospondin I, MMP13, NC4 domain of collagen IX, and interleukin-10, as well as basic cluster-containing polypeptides from PRELP, chondroadherin, and Oncostatin M; binding affinity depended on the number and position of sulfated tyrosine residues.","method":"Solid phase binding assay, ion-exchange chromatography fractionation, polypeptide interaction studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple binding partners tested with orthogonal fractionation and mutagenic-equivalent sulfation variants","pmids":["19700767"],"is_preprint":false},{"year":2008,"finding":"Osteoadherin overexpression in MC3T3E1 osteoblasts increased alkaline phosphatase activity, in vitro mineralization, and osteocalcin/osteoglycin expression while reducing proliferation and migration; knockdown had opposite effects, establishing OSAD as a functional regulator of osteoblast differentiation and maturation.","method":"Stable transfection (overexpression and shRNA knockdown), ALP activity assay, in vitro mineralization assay, qRT-PCR","journal":"Calcified tissue international","confidence":"Medium","confidence_rationale":"Tier 2 — clean gain- and loss-of-function with multiple phenotypic readouts in a single lab","pmids":["18496725"],"is_preprint":false},{"year":2006,"finding":"The proximal OMD promoter contains Smad-3, Smad-4, and AP-1 binding sites; TGF-β1 downregulates OSAD expression while BMP-2 upregulates it, establishing OSAD as a downstream transcriptional target of TGF-β family signaling in osteoblasts.","method":"In silico promoter analysis, TGF-β1 and BMP-2 stimulation assays, gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — promoter analysis combined with functional stimulation assays, single lab","pmids":["16970923"],"is_preprint":false},{"year":2002,"finding":"TGF-β1 stimulates OSAD synthesis and gene expression in mature odontoblasts and pulpal fibroblasts; TGF-β1 signaling components (TβRI, TβRII, SMAD-2, SMAD-3, SMAD-4) are present in human dental cells and maintained after culture, placing OSAD downstream of TGF-β1/Smad signaling in odontoblast matrix organization.","method":"Immunohistochemistry, RT-PCR, TGF-β1 stimulation of tooth slice and pulp explant cultures","journal":"Connective tissue research","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional stimulation with pathway component validation, single lab","pmids":["12489179"],"is_preprint":false},{"year":2019,"finding":"Overexpression of Omd in MC3T3-E1 osteoblasts increased cell viability and decreased caspase 3/7 activity (anti-apoptotic effect), while siRNA knockdown decreased viable cell numbers and increased caspase activity; BMP2 induces Omd expression via Smad1/Smad4 activation of the Omd promoter, demonstrated by reporter assay.","method":"Overexpression, siRNA knockdown, caspase 3/7 activity assay, luciferase reporter assay with Smad1/Smad4 co-transfection","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with reporter assay validation of transcriptional mechanism, single lab","pmids":["31638177"],"is_preprint":false},{"year":2013,"finding":"During endochondral bone formation, OSAD exists in two distinct pools with different glycosylation profiles: a non-mineral-bound pool lacking keratan sulfate chains, and a mineral-bound pool with increasing KS substitution as bone matures; sequential enzymatic digestions demonstrated these differences, suggesting distinct functional roles in directing mineralization.","method":"Quantitative gene expression, immunohistochemistry, electron microscopy, sequential enzymatic digestion of protein extracts","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods showing post-translational glycosylation differences with functional implications, single lab","pmids":["23337037"],"is_preprint":false},{"year":2012,"finding":"OSAD protein accumulates specifically in the predentin layer forming a gradient towards the mineralization front in developing mouse teeth; immunoelectron microscopy showed OSAD in close association with collagen fibers in predentin, suggesting a role in ECM organization prior to mineral deposition.","method":"Immunohistochemistry, immunogold electron microscopy (iEM) with quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with ultrastructural resolution and quantification tied to mineralization function","pmids":["22355375"],"is_preprint":false},{"year":2002,"finding":"Ultrastructural immunolocalization of OSAD in rat bone showed highest concentration at the border between bone and cartilage remnants in metaphyseal trabeculi, with distribution strikingly similar to bone sialoprotein (BSP), confirmed by double labeling; intracellular labeling was low, supporting an extracellular matrix role in mineralization.","method":"Immunohistochemistry, immunogold electron microscopy, quantitative marker density measurement, double labeling","journal":"Calcified tissue international","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative ultrastructural localization with double labeling for functional context","pmids":["12384815"],"is_preprint":false},{"year":2004,"finding":"αvβ3 integrin expression in human odontoblasts co-localizes with osteoadherin in predentin and the odontoblast layer; αvβ3 integrin appears first at intercellular contacts during in vitro odontoblast differentiation, suggesting OSAD mediates αvβ3-dependent odontoblast adhesion to the predentin/dentin matrix.","method":"Immunohistochemistry, in vitro odontoblast differentiation with antibody staining","journal":"Journal of dental research","confidence":"Low","confidence_rationale":"Tier 3 — co-localization without direct binding reconstitution; single lab","pmids":["15218045"],"is_preprint":false},{"year":2025,"finding":"ATF4 transcriptionally upregulates OMD (osteomodulin) by binding to its promoter region in human aortic smooth muscle cells undergoing calcification; OMD upregulation activates the PI3K/AKT signaling pathway, promoting osteogenic differentiation; AAV-mediated knockdown of ATF4 in vivo suppressed OMD expression and reduced vascular calcium deposition.","method":"Transcriptomic analysis, ChIP/promoter binding prediction (iRegulon), in vitro HASMC calcification model, in vivo AAV-shATF4 knockdown","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo validation with pathway analysis, single lab, no promoter mutagenesis","pmids":["41274065"],"is_preprint":false}],"current_model":"OMD (osteoadherin/osteomodulin) is a keratan sulfate-substituted small leucine-rich repeat proteoglycan (SLRP) expressed specifically in mineralized tissues (bone and dentin), where it promotes osteoblast adhesion via αvβ3 integrin, binds hydroxyapatite, associates with collagen fibrils at the mineralization front, and is transcriptionally regulated downstream of BMP-2/Smad1/4 (upregulation) and TGF-β1/Smad3 (downregulation); its overexpression enhances osteoblast differentiation, mineralization, and survival while its N-terminal tyrosine sulfate domain sequesters heparin-binding growth factors and matrix metalloproteinases in the extracellular matrix, and in vascular smooth muscle cells it is induced by ATF4 to activate PI3K/AKT-driven osteogenic differentiation promoting vascular calcification."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of OMD as a bone-specific keratan sulfate proteoglycan that binds hydroxyapatite and promotes αvβ3-integrin-mediated osteoblast attachment established it as a novel mineralized-tissue adhesion molecule distinct from previously known SLRPs.","evidence":"Protein purification from bovine bone, integrin affinity chromatography, cell attachment assays; cDNA cloning, Northern blot, and in situ hybridization confirming bone-restricted expression","pmids":["9566981","9642227"],"confidence":"High","gaps":["No in vivo loss-of-function model to confirm physiological necessity for mineralization","Mechanism by which OMD activates αvβ3 signaling downstream not characterized","Three-dimensional structure of the LRR domain not determined"]},{"year":2002,"claim":"Ultrastructural localization of OMD at the bone–cartilage border and in odontoblast predentin, co-distributing with BSP, placed OMD at the active mineralization front and extended its role from bone to dentin matrix organization.","evidence":"Immunogold electron microscopy with quantitative density measurements in rat bone; immunohistochemistry and TGF-β1 stimulation in human dental cells","pmids":["12384815","12489179"],"confidence":"Medium","gaps":["Direct physical interaction with BSP not demonstrated","Functional consequence of OMD removal at the mineralization front not tested","TGF-β1 regulation in dental cells appears opposite to later osteoblast data, unresolved"]},{"year":2006,"claim":"Demonstration that TGF-β1 downregulates and BMP-2 upregulates OMD transcription through Smad-binding elements in the proximal promoter established OMD as a transcriptionally regulated effector of TGF-β superfamily signaling in osteoblasts.","evidence":"In silico promoter analysis, TGF-β1 and BMP-2 stimulation assays with gene expression readouts","pmids":["16970923"],"confidence":"Medium","gaps":["No promoter mutagenesis to confirm functional necessity of individual Smad sites","Chromatin-level regulation (histone modifications, accessibility) not examined"]},{"year":2008,"claim":"Gain- and loss-of-function studies showing that OMD overexpression enhances ALP activity, mineralization, and osteocalcin expression while reducing proliferation established OMD as a functional driver—not merely a marker—of osteoblast differentiation.","evidence":"Stable overexpression and shRNA knockdown in MC3T3-E1 osteoblasts with ALP, mineralization, and qRT-PCR readouts","pmids":["18496725"],"confidence":"Medium","gaps":["Downstream signaling pathway activated by OMD overexpression not identified","In vivo bone phenotype of OMD overexpression or knockout not reported"]},{"year":2009,"claim":"Mapping of the tyrosine sulfate-rich N-terminal domain as a broad-spectrum binding module for heparin-binding proteins (bFGF-2, MMP13, TSP-I, IL-10) revealed a molecular mechanism by which OMD could sequester growth factors and proteinases in the pericellular matrix.","evidence":"Solid-phase binding assays with synthetic sulfated and unsulfated peptide variants","pmids":["19700767"],"confidence":"High","gaps":["Functional consequences of growth-factor sequestration on mineralization not tested in cells","Binding affinities not determined by solution-phase biophysics (SPR/ITC)","In vivo relevance of N-terminal interactions not validated"]},{"year":2013,"claim":"Discovery of two glycosylation-distinct OMD pools—a non-mineral-bound form lacking keratan sulfate and a mineral-bound form with increasing KS substitution—during endochondral ossification suggested that post-translational modification controls OMD's partitioning between matrix organization and mineral nucleation roles.","evidence":"Sequential enzymatic digestion, immunohistochemistry, and electron microscopy on developing bone","pmids":["23337037"],"confidence":"Medium","gaps":["Causal role of KS chains in hydroxyapatite binding not tested by deglycosylation reconstitution","Enzymatic machinery responsible for differential glycosylation not identified"]},{"year":2019,"claim":"Demonstration that BMP-2 induces OMD via Smad1/Smad4-dependent promoter activation, and that OMD overexpression is anti-apoptotic in osteoblasts, added a survival dimension to OMD's pro-osteogenic function and refined the transcriptional mechanism.","evidence":"Luciferase reporter assay with Smad1/Smad4 co-transfection, caspase 3/7 activity assays, siRNA knockdown in MC3T3-E1 cells","pmids":["31638177"],"confidence":"Medium","gaps":["Anti-apoptotic signaling pathway downstream of OMD not identified","Smad1/4 binding to endogenous OMD promoter not confirmed by ChIP"]},{"year":2025,"claim":"Identification of ATF4 as a transcriptional activator of OMD in vascular smooth muscle cells, with OMD activating PI3K/AKT to drive osteogenic transdifferentiation and vascular calcification, expanded OMD's pathological relevance beyond skeletal tissues.","evidence":"Transcriptomic analysis, iRegulon promoter prediction, in vitro HASMC calcification model, in vivo AAV-shATF4 knockdown reducing vascular calcium","pmids":["41274065"],"confidence":"Medium","gaps":["Direct ATF4 binding to OMD promoter not validated by ChIP-qPCR or mutagenesis","Mechanism by which OMD activates PI3K/AKT (receptor, adaptor) not identified","Whether integrin αvβ3 mediates OMD signaling in vascular cells untested"]},{"year":null,"claim":"No OMD knockout or loss-of-function animal model has been reported, leaving the in vivo necessity of OMD for skeletal mineralization, tooth development, and vascular calcification unestablished; the downstream signaling pathway by which OMD promotes osteoblast differentiation and survival also remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No genetic knockout or conditional deletion model in any organism","No structural model of the OMD leucine-rich repeat domain or hydroxyapatite-binding interface","No human genetic association linking OMD variants to skeletal or vascular disease"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,8,9]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,2,8,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,7,9]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,2,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7,8]}],"complexes":[],"partners":["ITGAV","ITGB3","FGF2","THBS1","MMP13","SMAD1","SMAD4","ATF4"],"other_free_text":[]},"mechanistic_narrative":"OMD (osteoadherin/osteomodulin) is a keratan sulfate-substituted small leucine-rich repeat proteoglycan that functions as a mineralization-associated extracellular matrix organizer and cell-adhesion molecule in bone and dentin. Its core protein contains 11 leucine-rich repeats, a highly acidic C-terminal domain, and six N-linked glycosylation sites; it binds hydroxyapatite, associates with collagen fibrils at the mineralization front, and promotes osteoblast and odontoblast attachment through integrin αvβ3 [PMID:9566981, PMID:22355375, PMID:12384815]. The tyrosine sulfate-rich N-terminal domain sequesters heparin-binding growth factors (bFGF-2), thrombospondin I, MMP13, and cytokines in the extracellular matrix, with binding affinity dependent on the number and position of sulfated tyrosine residues [PMID:19700767]. OMD expression is transcriptionally upregulated by BMP-2 via Smad1/Smad4 and by ATF4 in vascular smooth muscle cells, and its overexpression enhances osteoblast differentiation, mineralization, and survival while activating PI3K/AKT signaling during vascular calcification [PMID:31638177, PMID:18496725, PMID:41274065]."},"prefetch_data":{"uniprot":{"accession":"Q99983","full_name":"Osteomodulin","aliases":["Keratan sulfate proteoglycan osteomodulin","KSPG osteomodulin","Osteoadherin","OSAD"],"length_aa":421,"mass_kda":49.5,"function":"May be implicated in biomineralization processes. Has a function in binding of osteoblasts via the alpha(V)beta(3)-integrin","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q99983/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OMD","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OMD","total_profiled":1310},"omim":[{"mim_id":"618926","title":"OSTEOMODULIN; OMD","url":"https://www.omim.org/entry/618926"},{"mim_id":"613587","title":"OCCULT MACULAR DYSTROPHY; OCMD","url":"https://www.omim.org/entry/613587"},{"mim_id":"608643","title":"AROMATIC L-AMINO ACID DECARBOXYLASE DEFICIENCY; AADCD","url":"https://www.omim.org/entry/608643"},{"mim_id":"608135","title":"ASPORIN; ASPN","url":"https://www.omim.org/entry/608135"},{"mim_id":"602238","title":"EXOSOME COMPONENT 2; EXOSC2","url":"https://www.omim.org/entry/602238"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":63.3}],"url":"https://www.proteinatlas.org/search/OMD"},"hgnc":{"alias_symbol":["osteoadherin","SLRR2C"],"prev_symbol":[]},"alphafold":{"accession":"Q99983","domains":[{"cath_id":"3.80.10.10","chopping":"250-261_274-382","consensus_level":"medium","plddt":93.0244,"start":250,"end":382}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99983","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99983-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99983-F1-predicted_aligned_error_v6.png","plddt_mean":82.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OMD","jax_strain_url":"https://www.jax.org/strain/search?query=OMD"},"sequence":{"accession":"Q99983","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99983.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99983/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99983"}},"corpus_meta":[{"pmid":"15735689","id":"PMC_15735689","title":"Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15735689","citation_count":161,"is_preprint":false},{"pmid":"12075857","id":"PMC_12075857","title":"3-OMD and homocysteine plasma levels in parkinsonian patients.","date":"2002","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/12075857","citation_count":110,"is_preprint":false},{"pmid":"9566981","id":"PMC_9566981","title":"Bone matrix proteins: isolation and characterization of a novel cell-binding keratan sulfate proteoglycan (osteoadherin) from bovine bone.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9566981","citation_count":105,"is_preprint":false},{"pmid":"9642227","id":"PMC_9642227","title":"Osteoadherin, a cell-binding keratan sulfate proteoglycan in bone, belongs to the family of leucine-rich repeat proteins of the extracellular matrix.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9642227","citation_count":83,"is_preprint":false},{"pmid":"10656267","id":"PMC_10656267","title":"Super-motifs and evolution of tandem leucine-rich repeats within the small proteoglycans--biglycan, decorin, lumican, fibromodulin, PRELP, keratocan, osteoadherin, epiphycan, and osteoglycin.","date":"2000","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/10656267","citation_count":72,"is_preprint":false},{"pmid":"9880667","id":"PMC_9880667","title":"Nonpermissiveness for mouse embryonic stem (ES) cell derivation circumvented by a single backcross to 129/Sv strain: establishment of ES cell lines bearing the Omd conditional lethal mutation.","date":"1998","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/9880667","citation_count":67,"is_preprint":false},{"pmid":"18226951","id":"PMC_18226951","title":"Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis.","date":"2008","source":"Sleep medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18226951","citation_count":63,"is_preprint":false},{"pmid":"10913920","id":"PMC_10913920","title":"Expression of the small leucine-rich proteoglycan osteoadherin/osteomodulin in human dental pulp and developing rat teeth.","date":"2000","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/10913920","citation_count":52,"is_preprint":false},{"pmid":"19700767","id":"PMC_19700767","title":"The tyrosine sulfate-rich domains of the LRR proteins fibromodulin and osteoadherin bind motifs of basic clusters in a variety of heparin-binding proteins, including bioactive factors.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19700767","citation_count":41,"is_preprint":false},{"pmid":"18496725","id":"PMC_18496725","title":"Osteoadherin is upregulated by mature osteoblasts and enhances their in vitro differentiation and mineralization.","date":"2008","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/18496725","citation_count":33,"is_preprint":false},{"pmid":"12489179","id":"PMC_12489179","title":"TGF beta 1 signaling and stimulation of osteoadherin in human odontoblasts in vitro.","date":"2002","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/12489179","citation_count":30,"is_preprint":false},{"pmid":"12384815","id":"PMC_12384815","title":"Ultrastructural distribution of osteoadherin in rat bone shows a pattern similar to that of bone sialoprotein.","date":"2002","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/12384815","citation_count":29,"is_preprint":false},{"pmid":"12648264","id":"PMC_12648264","title":"Identification, distribution and expression of osteoadherin during tooth formation.","date":"2003","source":"European journal of oral sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12648264","citation_count":26,"is_preprint":false},{"pmid":"22355375","id":"PMC_22355375","title":"Osteoadherin accumulates in the predentin towards the mineralization front in the developing tooth.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22355375","citation_count":26,"is_preprint":false},{"pmid":"15218045","id":"PMC_15218045","title":"Alpha v beta 3 integrin expression in human odontoblasts and co-localization with osteoadherin.","date":"2004","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/15218045","citation_count":24,"is_preprint":false},{"pmid":"23337037","id":"PMC_23337037","title":"The glycosylation profile of osteoadherin alters during endochondral bone formation.","date":"2013","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/23337037","citation_count":22,"is_preprint":false},{"pmid":"16970923","id":"PMC_16970923","title":"Differential regulation of osteoadherin (OSAD) by TGF-beta1 and BMP-2.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16970923","citation_count":21,"is_preprint":false},{"pmid":"14673660","id":"PMC_14673660","title":"Immunodetection of osteoadherin in murine tooth extracellular matrices.","date":"2003","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14673660","citation_count":20,"is_preprint":false},{"pmid":"10607915","id":"PMC_10607915","title":"Tissue distribution of a novel cell binding protein, osteoadherin, in the rat.","date":"1999","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10607915","citation_count":15,"is_preprint":false},{"pmid":"37958408","id":"PMC_37958408","title":"Oligometastatic Disease (OMD): The Classification and Practical Review of Prospective Trials.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37958408","citation_count":10,"is_preprint":false},{"pmid":"31638177","id":"PMC_31638177","title":"Osteoadherin serves roles in the regulation of apoptosis and growth in MC3T3‑E1 osteoblast cells.","date":"2019","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31638177","citation_count":8,"is_preprint":false},{"pmid":"16387503","id":"PMC_16387503","title":"Heat-induced retrieval of immunogold labeling for nucleobindin and osteoadherin from Lowicryl sections of bone.","date":"2005","source":"Micron (Oxford, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/16387503","citation_count":7,"is_preprint":false},{"pmid":"31553751","id":"PMC_31553751","title":"Malaria transmission through the mosquito requires the function of the OMD protein.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31553751","citation_count":2,"is_preprint":false},{"pmid":"41274065","id":"PMC_41274065","title":"ATF4 transcriptional regulation of OMD and STC2 drives vascular calcification progression via the PI3K/AKT pathway.","date":"2025","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/41274065","citation_count":0,"is_preprint":false},{"pmid":"39280026","id":"PMC_39280026","title":"Identification of Potential Clusters of Signs and Symptoms to Prioritize Patients' Eligibility for AADCd Screening by 3-OMD Testing: An Italian Delphi Consensus.","date":"2024","source":"Behavioural neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39280026","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.15.659789","title":"Sequential Membrane Remodeling by Cholesterol Distinctly Modulates HCN Channels in Naïve and Neuropathic DRG Neurons","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.15.659789","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.18.658998","title":"RhoA activation promotes ordered membrane domain coalescence and suppresses neuronal excitability","date":"2025-06-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.18.658998","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.07.24308435","title":"The Effect of Metformin Treatment on the Circulating Proteome","date":"2024-06-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.07.24308435","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15301,"output_tokens":2868,"usd":0.044462},"stage2":{"model":"claude-opus-4-6","input_tokens":6274,"output_tokens":2620,"usd":0.145305},"total_usd":0.189767,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Osteoadherin (OMD/OSAD) was isolated from bovine bone as a keratan sulfate proteoglycan and shown to bind hydroxyapatite and promote osteoblast attachment in vitro as efficiently as fibronectin; cell binding was shown to be mediated specifically by integrin αvβ3, isolated by osteoadherin affinity chromatography of surface-iodinated osteoblast extracts.\",\n      \"method\": \"Protein purification, affinity chromatography, integrin isolation, in vitro cell attachment assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (purification, affinity chromatography, cell attachment assay) in a single foundational study with 105 citations\",\n      \"pmids\": [\"9566981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The primary structure of osteoadherin was determined, revealing 11 leucine-rich repeats, a highly acidic C-terminal domain, six N-linked glycosylation sites, and keratan sulfate chains; mRNA expression was restricted to bone (osteoblasts), confirmed by Northern blot and in situ hybridization.\",\n      \"method\": \"cDNA cloning, sequencing, Northern blot, in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — full primary structure determination with multiple validation methods, 83 citations\",\n      \"pmids\": [\"9642227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The tyrosine sulfate-rich N-terminal domain of osteoadherin binds heparin-binding proteins including bFGF-2, thrombospondin I, MMP13, NC4 domain of collagen IX, and interleukin-10, as well as basic cluster-containing polypeptides from PRELP, chondroadherin, and Oncostatin M; binding affinity depended on the number and position of sulfated tyrosine residues.\",\n      \"method\": \"Solid phase binding assay, ion-exchange chromatography fractionation, polypeptide interaction studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple binding partners tested with orthogonal fractionation and mutagenic-equivalent sulfation variants\",\n      \"pmids\": [\"19700767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Osteoadherin overexpression in MC3T3E1 osteoblasts increased alkaline phosphatase activity, in vitro mineralization, and osteocalcin/osteoglycin expression while reducing proliferation and migration; knockdown had opposite effects, establishing OSAD as a functional regulator of osteoblast differentiation and maturation.\",\n      \"method\": \"Stable transfection (overexpression and shRNA knockdown), ALP activity assay, in vitro mineralization assay, qRT-PCR\",\n      \"journal\": \"Calcified tissue international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean gain- and loss-of-function with multiple phenotypic readouts in a single lab\",\n      \"pmids\": [\"18496725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The proximal OMD promoter contains Smad-3, Smad-4, and AP-1 binding sites; TGF-β1 downregulates OSAD expression while BMP-2 upregulates it, establishing OSAD as a downstream transcriptional target of TGF-β family signaling in osteoblasts.\",\n      \"method\": \"In silico promoter analysis, TGF-β1 and BMP-2 stimulation assays, gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — promoter analysis combined with functional stimulation assays, single lab\",\n      \"pmids\": [\"16970923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TGF-β1 stimulates OSAD synthesis and gene expression in mature odontoblasts and pulpal fibroblasts; TGF-β1 signaling components (TβRI, TβRII, SMAD-2, SMAD-3, SMAD-4) are present in human dental cells and maintained after culture, placing OSAD downstream of TGF-β1/Smad signaling in odontoblast matrix organization.\",\n      \"method\": \"Immunohistochemistry, RT-PCR, TGF-β1 stimulation of tooth slice and pulp explant cultures\",\n      \"journal\": \"Connective tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional stimulation with pathway component validation, single lab\",\n      \"pmids\": [\"12489179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Overexpression of Omd in MC3T3-E1 osteoblasts increased cell viability and decreased caspase 3/7 activity (anti-apoptotic effect), while siRNA knockdown decreased viable cell numbers and increased caspase activity; BMP2 induces Omd expression via Smad1/Smad4 activation of the Omd promoter, demonstrated by reporter assay.\",\n      \"method\": \"Overexpression, siRNA knockdown, caspase 3/7 activity assay, luciferase reporter assay with Smad1/Smad4 co-transfection\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with reporter assay validation of transcriptional mechanism, single lab\",\n      \"pmids\": [\"31638177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"During endochondral bone formation, OSAD exists in two distinct pools with different glycosylation profiles: a non-mineral-bound pool lacking keratan sulfate chains, and a mineral-bound pool with increasing KS substitution as bone matures; sequential enzymatic digestions demonstrated these differences, suggesting distinct functional roles in directing mineralization.\",\n      \"method\": \"Quantitative gene expression, immunohistochemistry, electron microscopy, sequential enzymatic digestion of protein extracts\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods showing post-translational glycosylation differences with functional implications, single lab\",\n      \"pmids\": [\"23337037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"OSAD protein accumulates specifically in the predentin layer forming a gradient towards the mineralization front in developing mouse teeth; immunoelectron microscopy showed OSAD in close association with collagen fibers in predentin, suggesting a role in ECM organization prior to mineral deposition.\",\n      \"method\": \"Immunohistochemistry, immunogold electron microscopy (iEM) with quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with ultrastructural resolution and quantification tied to mineralization function\",\n      \"pmids\": [\"22355375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Ultrastructural immunolocalization of OSAD in rat bone showed highest concentration at the border between bone and cartilage remnants in metaphyseal trabeculi, with distribution strikingly similar to bone sialoprotein (BSP), confirmed by double labeling; intracellular labeling was low, supporting an extracellular matrix role in mineralization.\",\n      \"method\": \"Immunohistochemistry, immunogold electron microscopy, quantitative marker density measurement, double labeling\",\n      \"journal\": \"Calcified tissue international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative ultrastructural localization with double labeling for functional context\",\n      \"pmids\": [\"12384815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"αvβ3 integrin expression in human odontoblasts co-localizes with osteoadherin in predentin and the odontoblast layer; αvβ3 integrin appears first at intercellular contacts during in vitro odontoblast differentiation, suggesting OSAD mediates αvβ3-dependent odontoblast adhesion to the predentin/dentin matrix.\",\n      \"method\": \"Immunohistochemistry, in vitro odontoblast differentiation with antibody staining\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — co-localization without direct binding reconstitution; single lab\",\n      \"pmids\": [\"15218045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF4 transcriptionally upregulates OMD (osteomodulin) by binding to its promoter region in human aortic smooth muscle cells undergoing calcification; OMD upregulation activates the PI3K/AKT signaling pathway, promoting osteogenic differentiation; AAV-mediated knockdown of ATF4 in vivo suppressed OMD expression and reduced vascular calcium deposition.\",\n      \"method\": \"Transcriptomic analysis, ChIP/promoter binding prediction (iRegulon), in vitro HASMC calcification model, in vivo AAV-shATF4 knockdown\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo validation with pathway analysis, single lab, no promoter mutagenesis\",\n      \"pmids\": [\"41274065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OMD (osteoadherin/osteomodulin) is a keratan sulfate-substituted small leucine-rich repeat proteoglycan (SLRP) expressed specifically in mineralized tissues (bone and dentin), where it promotes osteoblast adhesion via αvβ3 integrin, binds hydroxyapatite, associates with collagen fibrils at the mineralization front, and is transcriptionally regulated downstream of BMP-2/Smad1/4 (upregulation) and TGF-β1/Smad3 (downregulation); its overexpression enhances osteoblast differentiation, mineralization, and survival while its N-terminal tyrosine sulfate domain sequesters heparin-binding growth factors and matrix metalloproteinases in the extracellular matrix, and in vascular smooth muscle cells it is induced by ATF4 to activate PI3K/AKT-driven osteogenic differentiation promoting vascular calcification.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OMD (osteoadherin/osteomodulin) is a keratan sulfate-substituted small leucine-rich repeat proteoglycan that functions as a mineralization-associated extracellular matrix organizer and cell-adhesion molecule in bone and dentin. Its core protein contains 11 leucine-rich repeats, a highly acidic C-terminal domain, and six N-linked glycosylation sites; it binds hydroxyapatite, associates with collagen fibrils at the mineralization front, and promotes osteoblast and odontoblast attachment through integrin αvβ3 [PMID:9566981, PMID:22355375, PMID:12384815]. The tyrosine sulfate-rich N-terminal domain sequesters heparin-binding growth factors (bFGF-2), thrombospondin I, MMP13, and cytokines in the extracellular matrix, with binding affinity dependent on the number and position of sulfated tyrosine residues [PMID:19700767]. OMD expression is transcriptionally upregulated by BMP-2 via Smad1/Smad4 and by ATF4 in vascular smooth muscle cells, and its overexpression enhances osteoblast differentiation, mineralization, and survival while activating PI3K/AKT signaling during vascular calcification [PMID:31638177, PMID:18496725, PMID:41274065].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of OMD as a bone-specific keratan sulfate proteoglycan that binds hydroxyapatite and promotes αvβ3-integrin-mediated osteoblast attachment established it as a novel mineralized-tissue adhesion molecule distinct from previously known SLRPs.\",\n      \"evidence\": \"Protein purification from bovine bone, integrin affinity chromatography, cell attachment assays; cDNA cloning, Northern blot, and in situ hybridization confirming bone-restricted expression\",\n      \"pmids\": [\"9566981\", \"9642227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo loss-of-function model to confirm physiological necessity for mineralization\",\n        \"Mechanism by which OMD activates αvβ3 signaling downstream not characterized\",\n        \"Three-dimensional structure of the LRR domain not determined\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Ultrastructural localization of OMD at the bone–cartilage border and in odontoblast predentin, co-distributing with BSP, placed OMD at the active mineralization front and extended its role from bone to dentin matrix organization.\",\n      \"evidence\": \"Immunogold electron microscopy with quantitative density measurements in rat bone; immunohistochemistry and TGF-β1 stimulation in human dental cells\",\n      \"pmids\": [\"12384815\", \"12489179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction with BSP not demonstrated\",\n        \"Functional consequence of OMD removal at the mineralization front not tested\",\n        \"TGF-β1 regulation in dental cells appears opposite to later osteoblast data, unresolved\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that TGF-β1 downregulates and BMP-2 upregulates OMD transcription through Smad-binding elements in the proximal promoter established OMD as a transcriptionally regulated effector of TGF-β superfamily signaling in osteoblasts.\",\n      \"evidence\": \"In silico promoter analysis, TGF-β1 and BMP-2 stimulation assays with gene expression readouts\",\n      \"pmids\": [\"16970923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No promoter mutagenesis to confirm functional necessity of individual Smad sites\",\n        \"Chromatin-level regulation (histone modifications, accessibility) not examined\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Gain- and loss-of-function studies showing that OMD overexpression enhances ALP activity, mineralization, and osteocalcin expression while reducing proliferation established OMD as a functional driver—not merely a marker—of osteoblast differentiation.\",\n      \"evidence\": \"Stable overexpression and shRNA knockdown in MC3T3-E1 osteoblasts with ALP, mineralization, and qRT-PCR readouts\",\n      \"pmids\": [\"18496725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway activated by OMD overexpression not identified\",\n        \"In vivo bone phenotype of OMD overexpression or knockout not reported\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping of the tyrosine sulfate-rich N-terminal domain as a broad-spectrum binding module for heparin-binding proteins (bFGF-2, MMP13, TSP-I, IL-10) revealed a molecular mechanism by which OMD could sequester growth factors and proteinases in the pericellular matrix.\",\n      \"evidence\": \"Solid-phase binding assays with synthetic sulfated and unsulfated peptide variants\",\n      \"pmids\": [\"19700767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequences of growth-factor sequestration on mineralization not tested in cells\",\n        \"Binding affinities not determined by solution-phase biophysics (SPR/ITC)\",\n        \"In vivo relevance of N-terminal interactions not validated\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of two glycosylation-distinct OMD pools—a non-mineral-bound form lacking keratan sulfate and a mineral-bound form with increasing KS substitution—during endochondral ossification suggested that post-translational modification controls OMD's partitioning between matrix organization and mineral nucleation roles.\",\n      \"evidence\": \"Sequential enzymatic digestion, immunohistochemistry, and electron microscopy on developing bone\",\n      \"pmids\": [\"23337037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal role of KS chains in hydroxyapatite binding not tested by deglycosylation reconstitution\",\n        \"Enzymatic machinery responsible for differential glycosylation not identified\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that BMP-2 induces OMD via Smad1/Smad4-dependent promoter activation, and that OMD overexpression is anti-apoptotic in osteoblasts, added a survival dimension to OMD's pro-osteogenic function and refined the transcriptional mechanism.\",\n      \"evidence\": \"Luciferase reporter assay with Smad1/Smad4 co-transfection, caspase 3/7 activity assays, siRNA knockdown in MC3T3-E1 cells\",\n      \"pmids\": [\"31638177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Anti-apoptotic signaling pathway downstream of OMD not identified\",\n        \"Smad1/4 binding to endogenous OMD promoter not confirmed by ChIP\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of ATF4 as a transcriptional activator of OMD in vascular smooth muscle cells, with OMD activating PI3K/AKT to drive osteogenic transdifferentiation and vascular calcification, expanded OMD's pathological relevance beyond skeletal tissues.\",\n      \"evidence\": \"Transcriptomic analysis, iRegulon promoter prediction, in vitro HASMC calcification model, in vivo AAV-shATF4 knockdown reducing vascular calcium\",\n      \"pmids\": [\"41274065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct ATF4 binding to OMD promoter not validated by ChIP-qPCR or mutagenesis\",\n        \"Mechanism by which OMD activates PI3K/AKT (receptor, adaptor) not identified\",\n        \"Whether integrin αvβ3 mediates OMD signaling in vascular cells untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No OMD knockout or loss-of-function animal model has been reported, leaving the in vivo necessity of OMD for skeletal mineralization, tooth development, and vascular calcification unestablished; the downstream signaling pathway by which OMD promotes osteoblast differentiation and survival also remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No genetic knockout or conditional deletion model in any organism\",\n        \"No structural model of the OMD leucine-rich repeat domain or hydroxyapatite-binding interface\",\n        \"No human genetic association linking OMD variants to skeletal or vascular disease\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 2, 8, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 2, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ITGAV\",\n      \"ITGB3\",\n      \"FGF2\",\n      \"THBS1\",\n      \"MMP13\",\n      \"SMAD1\",\n      \"SMAD4\",\n      \"ATF4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}