Osteoarthritis (OA) is an age-related musculoskeletal disorder lacking effective disease-modifying therapies. OA causes progressive disruption of the osteoimmune niche, a dynamic microenvironment where skeletal, vascular, stromal, and immune cells interact with extracellular matrix (ECM) components. Aging remodels this niche through chronic low-grade inflammation, cell senescence, immune dysfunction, vascular alterations, and aberrant mechanotransduction, creating a self-sustaining pathogenic tissue degeneration. The underlying mechanisms remain poorly understood.
This project aims to decipher the mechanisms underlying osteoimmune niche collapse, by developing innovative human aging minibone models reproducing the cellular, mechanical, vascular, and immune complexity of osteoarthritic tissues. We hypothesize that hubs linking mechanobiological, inflammatory, and immune pathways, including Gremlin-1 (GREM1), secreted phospholipases A2 (sPLA2s), diacylglycerol kinases (DGKs), and dysfunctional cytotoxic T lymphocytes (CTLs), drive disease progression and represent actionable therapeutic targets.
The project brings together integrating expertises in mechanobiology, ECM biology, vascular remodeling, osteoclast and T-cell biology, lipid signaling, immune synapse organization, advanced imaging, and multi-omics technologies. The consortium, comprising the University of Brescia, the Institute of Biochemistry and Cell Biology of the CNR, the University of Piemonte Orientale, and the University of Siena, will enable a systems-level investigation of OA as an aging-associated disease.
The four scientific milestones include the investigation of how ECM remodeling, altered biomechanics, and vascular dysfunction promote disease progression. Mechanobiological models of aging-associated OA will be developed, from GREM1-remodeled ECMs to multicellular 3D minibones, integrating skeletal, vascular, stromal, and immune components. The role of sPLA2s will be defined in inflammatory osteoclastogenesis and bone inflammaging, identifying lipid-mediated mechanisms underlying pathological bone remodeling. We will evaluate whether targeting DGKα and DGKζ can restore signaling competence and functional fitness in senescent and exhausted T cells. Then, elucidating how the senescent microenvironment impairs CTL-mediated immune surveillance, we will identify strategies to restore cytotoxic precision.
A major outcome will be human aging models that in conjunction with advanced imaging, extracellular vesicle profiling, computational modeling, and multi-omics techniques, will provide an innovative platform to investigate the interplay among mechanobiology, inflammation, immunity, and aging. The project is expected to identify novel therapeutic targets and broadly applicable research tools for aging-associated diseases. Training, dissemination, workshops, and scientific webinars will maximize impact and support the younger researchers in osteoimmunology and precision medicine.
This project aims to decipher the mechanisms underlying osteoimmune niche collapse, by developing innovative human aging minibone models reproducing the cellular, mechanical, vascular, and immune complexity of osteoarthritic tissues. We hypothesize that hubs linking mechanobiological, inflammatory, and immune pathways, including Gremlin-1 (GREM1), secreted phospholipases A2 (sPLA2s), diacylglycerol kinases (DGKs), and dysfunctional cytotoxic T lymphocytes (CTLs), drive disease progression and represent actionable therapeutic targets.
The project brings together integrating expertises in mechanobiology, ECM biology, vascular remodeling, osteoclast and T-cell biology, lipid signaling, immune synapse organization, advanced imaging, and multi-omics technologies. The consortium, comprising the University of Brescia, the Institute of Biochemistry and Cell Biology of the CNR, the University of Piemonte Orientale, and the University of Siena, will enable a systems-level investigation of OA as an aging-associated disease.
The four scientific milestones include the investigation of how ECM remodeling, altered biomechanics, and vascular dysfunction promote disease progression. Mechanobiological models of aging-associated OA will be developed, from GREM1-remodeled ECMs to multicellular 3D minibones, integrating skeletal, vascular, stromal, and immune components. The role of sPLA2s will be defined in inflammatory osteoclastogenesis and bone inflammaging, identifying lipid-mediated mechanisms underlying pathological bone remodeling. We will evaluate whether targeting DGKα and DGKζ can restore signaling competence and functional fitness in senescent and exhausted T cells. Then, elucidating how the senescent microenvironment impairs CTL-mediated immune surveillance, we will identify strategies to restore cytotoxic precision.
A major outcome will be human aging models that in conjunction with advanced imaging, extracellular vesicle profiling, computational modeling, and multi-omics techniques, will provide an innovative platform to investigate the interplay among mechanobiology, inflammation, immunity, and aging. The project is expected to identify novel therapeutic targets and broadly applicable research tools for aging-associated diseases. Training, dissemination, workshops, and scientific webinars will maximize impact and support the younger researchers in osteoimmunology and precision medicine.