Bone is continuously regenerated through a process known as bone remodeling, in which osteoblasts (bone-forming cells) build new bone and osteoclasts (bone-resorbing cells) remove old mineralized tissue. Maintaining a balance between these two cell types is essential for skeletal strength and fracture prevention. When this balance is disrupted, osteoporosis and other metabolic bone diseases can occur. Vitamin K has long been associated with bone health, but its precise biological role remains unknown. Therefore, scientists have sought to understand the molecular pathways by which vitamin K regulates skeletal homeostasis.
To address this challenge, a research team led by Dr. Matthew Ferron, director of the Molecular Physiology Research Unit at the Clinical Research Institute of Montreal (IRCM) in Canada, investigated how vitamin K-dependent γ-carboxylation modulates communication between osteoblasts and osteoclasts. The researchers investigated how vitamin K-dependent proteins influence bone remodeling using genetically engineered mouse models, osteoblast-osteoclast co-culture systems, molecular signaling analyses, histology, and micro-computed tomography imaging. Their findings were published in Volume 14 of the journal on April 28, 2026. bone research.
The research team first investigated the enzyme responsible for vitamin K-dependent gamma-carboxylation. They found that the enzymes γ-glutamyl carboxylase and vitamin K oxidoreductase were expressed primarily in osteoblasts rather than osteoclasts, suggesting that vitamin K signaling acts primarily through bone-forming cells. To investigate this pathway, the researchers selectively deleted gamma-glutamyl carboxylase from osteoblasts of male mice. By 6 months of age, these mice had significantly increased bone mass and a denser, more interconnected bone structure.
Further analysis revealed that the increase in bone mass was mainly caused by decreased bone resorption rather than enhanced bone formation. Loss of osteoblast-specific γ-glutamyl carboxylase significantly reduced osteoclast number and surface area, with a concomitant reduction in circulating markers of bone resorption. In co-culture experiments, osteoblasts lacking γ-glutamyl carboxylase were significantly less effective in supporting osteoclastogenesis.
The researchers next looked for gamma-carboxylated proteins that could link osteoblasts to osteoclasts. Their analysis identified growth arrest specific 6 (GAS6), a signaling molecule secreted by osteoblasts and activating TAM family receptors, AXL and MerTK on preosteoclasts. Recombinant γ-carboxylated GAS6 strongly promoted osteoclast formation, increased the number of nuclei per osteoclast, and produced larger multinucleated cells that could promote bone resorption. Pharmacological inhibition of AXL and MerTK receptors significantly suppressed osteoclast generation, confirming the importance of the GAS6-TAM signaling pathway.
“Our findings reveal an unexpected mechanism by which osteoblasts actively control osteoclast maturation.” Dr. Ferron says. ”vitamin K dependence γ-Carboxylation not only influences bone mineralization; It also controls how osteoblasts communicate with osteoclast precursor cells through GAS6 signaling. ”
Determining whether elevated GAS6 can directly alter skeletal remodeling aliveResearchers studied transgenic mice with increased circulating GAS6 levels. These animals exhibited the opposite phenotype, including decreased bone density, increased osteoclast numbers, and enhanced bone resorption. Additional experiments showed that GAS6 primarily promotes the fusion of preosteoclasts into mature multinucleated osteoclasts, rather than altering osteoclast differentiation per se.
“This study provides a new framework for understanding how vitamin K affects skeletal biology.” Dr. Ferron explains. ”Targeting GAS6 or TAM receptor signaling may ultimately help regulate excessive bone resorption while maintaining normal bone remodeling. ”
This finding may have important clinical implications. In the long term, identification of the GAS6-TAM signaling axis may support the development of treatments for osteoporosis and other diseases characterized by excessive osteoclast activity.
Overall, this study identified a previously unknown vitamin K-dependent pathway by which osteoblasts regulate osteoclast maturation and bone resorption. By identifying GAS6 as a mediator linking osteoblasts and osteoclasts, this study advances our understanding of skeletal homeostasis and opens new possibilities for therapies targeting bone fragility and metabolic bone diseases.
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Reference magazines:
Pata, M. others. (2026). In male mice, vitamin K-dependent carboxylation in osteoblasts regulates GAS6-mediated bone resorption. Bone research. DOI: 10.1038/s41413-026-00528-2. https://www.nature.com/articles/s41413-026-00528-2
