Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction

by Selleckchem | Nov 29 2023

Regeneration of alveolar bone is an essential step in restoring healthy function following tooth extraction. Growth of new bone in the healing extraction socket can be variable and often unpredictable when systemic comorbidities are present, leading to the need for additional therapeutic targets to accelerate the regenerative process. One such target is the TAM family (Tyro3, Axl, Mertk) of receptor tyrosine kinases. These proteins have been shown to help resolve inflammation and maintain bone homeostasis and thus may have therapeutic benefits in bone regeneration following extraction. Treatment of mice with a pan-TAM inhibitor (RXDX-106) led to accelerated alveolar bone fill following first molar extraction in a mouse model without changing immune infiltrate. Treatment of human alveolar bone mesenchymal stem cells with RXDX-106 upregulated Wnt signaling and primed the cells for osteogenic differentiation. Differentiation of human alveolar bone mesenchymal stem cells with osteogenic media and TAM-targeted inhibitor RXDX-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific) showed enhanced mineralization with pan-TAM or Mertk-specific inhibitors and no change with Axl-specific inhibitor. First molar extractions in Mertk-/- mice had increased alveolar bone regeneration in the extraction socket relative to wild type controls 7 d postextraction. Flow cytometry of 7-d extraction sockets showed no difference in immune cell numbers between Mertk-/- and wild type mice. RNAseq of day 7 extraction sockets showed increased innate immune-related pathways and genes associated with bone differentiation in Mertk-/- mice. Together, these results indicate that TAM receptor signaling, specifically through Mertk, can be targeted to enhance bone regeneration after injury.

Comments:

The information you provided discusses a study that explores the role of TAM receptors (Tyro3, Axl, Mertk) in promoting alveolar bone regeneration following tooth extraction. The study demonstrates that these receptor proteins play a crucial role in resolving inflammation and maintaining bone homeostasis. The researchers used a pan-TAM inhibitor (RXDX-106) to accelerate alveolar bone fill in a mouse model after tooth extraction. Additionally, treatment with this inhibitor enhanced mineralization in human alveolar bone mesenchymal stem cells and upregulated Wnt signaling, which is important for osteogenic differentiation.

Furthermore, the study identified Mertk, a specific TAM receptor, as a key player in bone regeneration. Mice lacking the Mertk gene showed increased alveolar bone regeneration after tooth extraction compared to wild-type mice. The researchers found that targeting Mertk led to enhanced bone regeneration without affecting immune cell numbers in the extraction site. RNA sequencing analysis revealed increased innate immune-related pathways and genes associated with bone differentiation in Mertk-deficient mice, indicating the involvement of Mertk in these processes.

In summary, the study suggests that TAM receptor signaling, particularly through Mertk, can be targeted to enhance bone regeneration after injury, providing potential therapeutic avenues for improving outcomes following tooth extraction, especially in cases where the regenerative process is impaired due to systemic comorbidities.