{
  "abstract": "Vitamin D receptor (VDR) signaling is essential for osteoblast maturation and skeletal mineralization, yet the intracellular mechanisms linking VDR activity to matrix production remain poorly defined. Here, we show that vdr-/- calvarial osteoblasts initiate differentiation but fail to complete the transition to a mature, mineralizing state, exhibiting suppressed late-stage markers such as Dmp1, Phex, and Col1a1 and defective nodule formation both in vivo and in vitro. Transcriptomic profiling revealed a SMAD network imbalance, with elevated inhibitory SMADs and attenuated phosphorylation of both SMAD1/5/9 and SMAD2/3. Whereas SMAD1/5/9 activation was preserved in vivo and restored by exogenous BMP2 in vitro, consistent with in vivo paracrine BMP availability, reduced SMAD2/3 phosphorylation persisted in both contexts, indicating a cell-autonomous defect. Mechanistically, vdr-/- osteoblasts displayed impaired intracellular Ca2+ dynamics and diminished CaMKII activation, with VDR/RXR occupancy detected near the Camk2g locus. Pharmacological CaMKII inhibition (KN-93) recapitulated the phenotype, reducing SMAD2/3 phosphorylation and mineralization and establishing CaMKII as an upstream regulator of SMAD2/3. A milk-based diet rescued skeletal defects in vdr-/- mice in a calcium-independent manner and selectively restored CaMKII-SMAD2/3 signaling. Metabolomic profiling identified the omega-6 fatty acid y-linolenic acid (GLA) as an elevated circulating mediator; exogenous GLA restored Ca2+ flux, CaMKII activation, SMAD2/3 phosphorylation, matrix production, and mineralization, without reactivating Runx2, Sp7, or BMP-SMAD1/5/9 signaling, and dependent on CaMKII activity. These findings reveal a VDR-independent, GLA-inducible CaMKII-SMAD2/3 mineralization program, positioning metabolic modulation of calcium signaling as a strategy to restore osteoblast function under impaired vitamin D signaling.",
  "abstract_shown": true,
  "affiliations": [
    "Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "T. Biswas"
    },
    {
      "name": "C. Chongtham"
    },
    {
      "name": "N. Kumari"
    },
    {
      "name": "Y. Saneja"
    },
    {
      "name": "N. K. Yadav"
    },
    {
      "name": "J. S. Maras"
    },
    {
      "name": "S. S. Kamat"
    },
    {
      "affs": [
        0
      ],
      "name": "G. A. Arimbasseri"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cngp7brzjz76z.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.06.10.731289",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731289v2.full",
  "id": "cngp7brzjz76z",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731289v2",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "physiology"
    ],
    [
      "openalex",
      "1312|Bone Metabolism and Diseases"
    ]
  ],
  "openalex": "W7164548051",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731289v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cngp7brzjz76z.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:32Z",
      "native_id": "10.64898/2026.06.10.731289",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731289v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:physiology",
      "subfield": "physiology"
    }
  ],
  "title": "γLinolenic Acid Induces a Vitamin D Receptor-Independent Mineralization Program by Activating CaMKII--SMAD2/3 Pathway in Calvarial Osteoblasts",
  "title_text": "γLinolenic Acid Induces a Vitamin D Receptor-Independent Mineralization Program by Activating CaMKII--SMAD2/3 Pathway in Calvarial Osteoblasts",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:32Z",
  "url": "https://research.draconitic.com/paper/cngp7brzjz76z",
  "venue": "bioRxiv",
  "versions": []
}