Focal adhesion kinase inhibitors prevent osteoblast mineralization in part due to suppression of Akt-mediated stabilization of osterix

Gunn, Scott A.; Kreps, Lauren M.; Zhao, Huijun; Landon, Katelyn; Ilacqua, Jacob S.; Addison, Christina L.

doi:10.1016/j.jbo.2022.100432

Cited by 3 publications

(3 citation statements)

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“…Previous research has indicated that prolonged, elevated inflammation at the site of musculoskeletal trauma is one of the key contributors to impaired wound healing and development of heterotopic ossification (HO) ( 7 , 8 , 44 , 45 , 57 , 59 , 67 – 70 ). As an important regulator of cytokine and integrin-mediated signaling, FAK2 is involved in various cellular processes including cell adhesion, motility, proliferation, osteogenesis and bone homeostasis, through its kinase activity and scaffolding functions under steady and pathologic states ( 22 , 23 , 71 – 74 ). Tourniquet-induced ischemia-related injury (IR) exacerbates trauma-mediated musculoskeletal tissue injury, inflammation, osteogenic progenitor cell development and HO formation.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier studies demonstrate FAK adhesion-dependent signaling is critical for new bone formation, as it promotes osteoblast progenitor proliferation, differentiation, and mechanotransduction through enhancement of Akt, mTOR and WNT signaling ( 22 , 23 , 74 , 76 , 77 ). MSCs engineered to over-express FAK exhibit a marked increase in their osteogenic potential in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…The integrin-associated cytoplasmic protein tyrosine kinase, focal adhesion kinase-2 (FAK2), has been shown to be a key player of early signaling that orchestrates the initial development of focal adhesions. FAK2 has been shown to play important roles in the adherence of cells to the extracellular matrix (ECM) and cellular processes such cell adhesion, migration, proliferation, cytoskeletal organization, differentiation, and survival (20)(21)(22)(23). FAK activity is regulated through extracellular integrin-ECM interactions and transmembrane receptors (G-protein-coupled, cytokine and growth factor receptors) at the plasma membrane), leading to downstream activation of phosphatidylinositol 3-kinase (PI3K) and AKT1, MAPK1/ERK2, MAPK3/ERK1 and MAP kinase signaling cascades (24).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of focal adhesion kinase 2 results in a macrophage polarization shift to M2 which attenuates local and systemic inflammation and reduces heterotopic ossification after polysystem extremity trauma

Rowe,

Nwaolu,

Salinas

et al. 2023

Front. Immunol.

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IntroductionHeterotopic ossification (HO) is a complex pathology often observed in combat injured casualties who have sustained severe, high energy polytraumatic extremity injuries. Once HO has developed, prophylactic therapies are limited outside of surgical excision. Tourniquet-induced ischemia injury (IR) exacerbates trauma-mediated musculoskeletal tissue injury, inflammation, osteogenic progenitor cell development and HO formation. Others have shown that focal adhesion kinase-2 (FAK2) plays a key role in regulating early inflammatory signaling events. Therefore, we hypothesized that targeting FAK2 prophylactically would mitigate extremity trauma induced IR inflammation and HO formation.MethodsWe tested whether the continuous infusion of a FAK2 inhibitor (Defactinib, PF-573228; 6.94 µg/kg/min for 14 days) can mitigate ectopic bone formation (HO) using an established blast-related extremity injury model involving femoral fracture, quadriceps crush injury, three hours of tourniquet-induced limb ischemia, and hindlimb amputation through the fracture site. Tissue inflammation, infiltrating cells, osteogenic progenitor cell content were assessed at POD-7. Micro-computed tomography imaging was used to quantify mature HO at POD-56.ResultsIn comparison to vehicle control-treated rats, FAK2 administration resulted in no marked wound healing complications or weight loss. FAK2 treatment decreased HO by 43%. At POD-7, marked reductions in tissue proinflammatory gene expression and assayable osteogenic progenitor cells were measured, albeit no significant changes in expression patterns of angiogenic, chondrogenic and osteogenic genes. At the same timepoint, injured tissue from FAK-treated rats had fewer infiltrating cells. Additionally, gene expression analyses of tissue infiltrating cells resulted in a more measurable shift from an M1 inflammatory to an M2 anti-inflammatory macrophage phenotype in the FAK2 inhibitor-treated group.DiscussionOur findings suggest that FAK2 inhibition may be a novel strategy to dampen trauma-induced inflammation and attenuate HO in patients at high risk as a consequence of severe musculoskeletal polytrauma.

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