Researchers found that FGFR1 signaling helps organize bone-building material and cellular connections needed for newly embedded bone cells to survive

Bone cells called osteocytes help maintain skeletal strength, but how newly formed osteocytes survive remains unclear. Researchers at Washington University School of Medicine found that removing FGFR1 signaling in adult mice disrupted the bone matrix and cellular projections needed for osteocyte communication, leading to cell death in newly formed bone. The findings identify a link between bone matrix organization, osteocyte maturation and survival, offering a foundation for future studies of age-related bone fragility.

Osteocytes are the most abundant cells in mature bone and help maintain skeletal health by coordinating bone formation and breakdown. These long-lived cells sit inside the mineralized bone matrix and extend slender projections through tiny channels, allowing them to communicate with neighboring bone cells and blood vessels. Osteocyte loss is associated with fragile bones, but how these cells form and survive remains unclear.

Addressing this challenge, a research team was led by Professor David M. Ornitz from the Department of Developmental Biology, Washington University School of Medicine, St. Louis, USA. The researchers investigated fibroblast growth factor receptor 1 (FGFR1), a protein involved in skeletal development, by selectively inactivating its gene in the mature bone-cell lineage of adult mice. They examined bone tissues for cell death, differentiation markers, cellular projections and matrix structure, and analyzed gene activity in mouse cortical bone and Ocy454 osteocyte-like cells. They also stimulated new bone formation through mechanical loading to determine whether the effects depended on where bone was being formed. Their findings were published on September 7, 2026, in Volume 14 of the journal Bone Research.

The team found that losing FGFR1 signaling led to osteocyte death, but the effect was concentrated in newly formed bone rather than pre-existing bone. Dying cells retained markers normally associated with bone-forming cells or early osteocyte development, suggesting that the transition into fully mature osteocytes was disrupted. The researchers also observed fewer cellular projections and a substantial loss of the lacunocanalicular network, the microscopic communication system that connects osteocytes with their surroundings. When mechanical loading stimulated new bone formation at a different bone surface, osteocyte death also appeared in that newly formed region.

Further experiments pointed to the surrounding bone matrix as a key part of the problem. The team found a thinner layer of osteoid, the collagen-rich material deposited before it becomes mineralized bone, alongside reduced levels of matrix components. Microscopy revealed disorganized collagen fibers and structural abnormalities in newly forming bone. These changes were detectable as early as three weeks after FGFR1 inactivation, when relatively few dying osteocytes were present, suggesting that matrix disruption may precede and contribute to cell death. In laboratory-grown osteocyte-like cells, stimulating FGF signaling encouraged longer cellular projections, whereas blocking the pathway shortened them.

“FGFR1 signaling appears to help newly embedded osteocytes survive by supporting the organization of the surrounding bone matrix and the cellular projections they need to connect with their environment,” said first author Professor Debabrata Patra.

Gene-expression analyses supported this explanation. In mouse cortical bone and cultured osteocyte-like cells, disrupting FGFR signaling altered genes involved in extracellular matrix organization, collagen formation, skeletal development, and neuronal pathways associated with cellular projections. The overlapping changes suggest that FGFR signaling coordinates both the surrounding matrix and cellular gene-expression programs involved in osteocyte maturation. Inactivating FGFR1 specifically in mature osteocytes did not produce a comparable cell-death phenotype, highlighting the importance of FGFR1 during the transition to newly embedded osteocytes.

“These findings highlight the importance of studying the earliest stages of osteocyte maturation to understand how bone tissue develops and maintains its structure,” said Prof. Ornitz.

These findings may help guide future research into how bone aging and fragility develop. However, the study used mouse models and laboratory-grown cells; it does not establish a treatment for people or demonstrate that manipulating FGFR1 can prevent human bone loss.

Overall, the study identifies FGFR1 signaling as an important regulator of the bone matrix, cellular projections and survival of newly formed osteocytes. By showing how defects in the newly forming bone environment coincide with impaired cell maturation and death, the findings provide a basis for investigating how healthy bone tissue is built and maintained, and why this process may fail with age.

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Reference
Title of original paper: Fibroblast growth factor receptor signaling in maturing osteoblasts controls cell-matrix interactions critical for osteocyte survival
Journal: Bone Research
DOI: 10.1038/s41413-026-00583-9

About Washington University School of Medicine, USA
Washington University School of Medicine, located in St. Louis, Missouri, USA, is an academic medical institution dedicated to advancing human health through scientific discovery, medical education, and patient care. Founded in 1891, it brings together researchers, physicians, educators, and students across diverse biomedical disciplines. The institution supports basic, translational, and clinical research, encouraging collaboration to improve understanding of disease and develop better approaches to prevention, diagnosis, and treatment. Its educational programs train future physicians and biomedical scientists, while its clinical teams provide care through affiliated hospitals and regional facilities.
Visit: https://medicine.washu.edu/

About Professor David M. Ornitz
Prof. David M. Ornitz is an Alumni Endowed Professor in the Department of Developmental Biology at Washington University School of Medicine, St. Louis, Missouri, USA. He is recognized for seminal discoveries in fibroblast growth factor (FGF) signaling and for defining the functions of FGFs in embryonic development and adult tissues. He earned his PhD in Biochemistry from the University of Washington, Seattle, in 1987 and completed postdoctoral training in Genetics at Harvard Medical School in 1992. He has published more than 160 scientific papers and 26 book chapters and reviews, contributing significantly to scientific understanding of FGF biology.

Funding Information
This work was supported by National Institutes of Health grant R01 AR079246 (D.M.O.), R01 AR066590 (D.P.), R01 DK116716 (M.W.), R01 AR047867 (M.J.S.), T32 DK007028 and F32 AR081660 (C.M.M.) and the Washington University Musculoskeletal Research Center (P30 AR074992). M.N.W. acknowledges funding support from the Smith Family Foundation Odyssey Award and the Chen Institute Massachusetts General Hospital Research Scholar (2024-2029) award. SEM and TEM imaging were performed at the Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642).