Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction

Abstract

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.

Keywords

osteogenesis osteoblasts inflammation wound healing RXDX-106

Introduction

Loss of teeth due to disease or traumatic injury remains a significant health care burden worldwide (Eke et al. 2016). Partial or complete edentulism results in a loss of oral function and aesthetic concerns, which diminishes quality of life. Furthermore, regeneration of tissue lost after extraction (e.g., alveolar bone) is not predictable, partially due to the complexity of the regenerative process, particularly when systemic comorbidities are present (Sculean et al. 2008). For alveolar bone regeneration to be successful, the oral tissues must navigate 3 components of the regenerative process: wound healing, resolution of endogenous inflammation, and promotion of growth and differentiation of the native bone tissue (Kornman and Robertson 2000). Soluble factors and bone-grafting additives that focus on a single aspect of the regenerative process are the current standard of care to enhance regenerative success but remain limited by adverse side effects and unpredictable efficacy in generalized populations. New factors and therapies that target the entire regenerative process will form the basis for a new generation of biomedical regenerative approaches.

One potential therapeutic target in alveolar bone regeneration is the TAM family (Tyro3, Axl, Mertk) of receptor tyrosine kinases. Binding of TAM receptors by their ligand Gas6 or protein S results in dimerization and phosphorylation of the tyrosine kinase cytosol residues and activation of the intracellular signaling cascade via phosphatidylinositol 3-kinase (PI3K). TAM receptor signaling has been implicated in wound-healing processes such as thrombogenesis (Angelillo-Scherrer et al. 2001), resolution of inflammation (Nassar et al. 2017), and bone metastasis (Decker et al. 2017). These previous studies suggest that TAM receptor signaling is potentially a potent regulator of bone regeneration. However, the role of TAM receptors in alveolar bone regeneration in the context of tooth extraction sockets has not been elucidated.

The present study focused on evaluating the TAM family of receptors as therapeutic targets in alveolar bone regeneration. We hypothesized that inhibition of TAM receptor signaling would prime alveolar bone toward a regenerative phenotype and that targeting these receptors with small molecule inhibitors would accelerate alveolar bone fill following extraction. These studies will provide a basis for potential TAM-targeted therapies in alveolar bone regeneration.

Materials and Methods

Animals

All animal studies were performed with the ARRIVE guidelines. This study used male and female C57BL/6j mice or Mertk ^–/– mice on a C57BL/6j background (Jackson Laboratories). Mice were maintained in accordance with institutional animal care and use guidelines, and experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Michigan. Animals were housed at a density of 4 or 5 mice per cage and with accordance to the specific pathogen-free conditions. Six-week-old mice were anesthetized and the left maxillary first molar extracted. Mice were monitored daily for the duration of the experiment and euthanized at day 7 following tooth extraction. Tissues were analyzed in a blinded manner; investigators were not blinded during treatment administration. Time points were selected to evaluate early stages of alveolar socket healing/wound repair and with guidance from a previously reported murine extraction study (Michalski et al. 2019). For TAM inhibitor studies, RXDX-106 (Selleckchem) was administered at a dose of 50 mg/kg daily by oral gavage, starting immediately prior to extraction, and mice were separated by cage into 2 treatment groups. All experiments were conducted with n ≥ 5 to be sufficiently powered to detect a 50% change in bone healing or immune populations with power >80%. A priori exclusion criteria were signs of infection following extraction.

Flow Cytometry Analysis

Mice were euthanized, and an intracardiac injection of 30 mL of sterile saline was used to flush vessels of erythrocytes and other hematopoietic lineage cells. Gingival tissue was harvested and processed per a previously reported method (Dutzan et al. 2016). Once a single-cell suspension of gingival cells was obtained, cells were slowly mixed into a 40% Percoll/RPMI-Complete solution. This solution was then layered on top of 75% Percoll/RPMI-Complete solution (17-0891; GE Healthcare) and centrifuged for 20 min. The buffy coat layer was removed and added to RPMI-Complete. Supernatant was aspirated and resuspended in flow buffer (1× phosphate-buffered saline + 1% fetal bovine serum; Gibco). Samples were then incubated for 30 min with flow cytometry antibodies (BV421-Ly6g 1:250, FITC-CD11b 1:250, PE-B220 1:250, PercP/Cy5.5-CD4 1:250, PE/Cy7-CD8 1:1,000, APC-Lys6C 1:250, Fc-BLOCK 1:250; BioLegend) and live/dead stain (1:1,000; BioLegend).

Micro–computed Tomography

Maxillae were harvested at sacrifice, fixed in 10% neutral-buffered formalin 24 to 48 h at 4 °C on a rocker, and stored in 70% ethanol. Samples were scanned by micro–computed tomography (μCT; 12-µm voxel size, 70 KVp; µCT-100 [Scanco]) as described previously (Michalski et al. 2019).

Histology

Maxillae were fixed in 10% neutral-buffered formalin 24 to 48 h at 4 °C on a rocker, decalcified in 14% EDTA for 10 to 20 d, embedded in paraffin, and sectioned at 5 µm. A sagittal section of the maxilla was cut to view extraction sockets and interradicular bone and then stained with hematoxylin and eosin or trichrome staining. For immunohistochemistry, primary antibodies rat anti-F4/80 (Abcam), rabbit anti-iNOS (Abcam), and goat anti-MMR (R&D Systems) were diluted 1:200 and incubated overnight at 4 °C. After washing, secondary antibodies goat anti-rat Cy3 (BioLegend), goat anti-rabbit AlexaFluor647 (Invitrogen), and rabbit anti-goat AlexaFluor488 (Abcam), respectively, were diluted 1:200 and incubated for 45 min in the dark. Sections were washed and coverslips mounted with ProLong Gold with DAPI. Images were captured on a Leica Thunder fluorescent microscope. Images were processed through ImageJ (National Institutes of Health).

In Vitro Osteoblast Differentiation

Human alveolar bone mesenchymal stem cells (MSCs) were obtained in accordance with Institutional Review Board protocol HUM00142680. Cultures were established for 48 h, followed by addition of 50 μg/mL of ascorbic acid and 10mM β-glycerophosphate. Inhibition of TAM receptor signaling was accomplished through addition of a TAM/MET–specific inhibitor: TAMi (RXDX-106, 10 nM [SelleckChem]; Yokoyama et al. 2019). Specific receptor inhibition of Mertk and Axl was achieved with respective inhibitors: Mertki (MRX-2843, 100nM; Minson et al. 2016) and Axli (ASP-2215, 10 nM [SelleckChem]; Mori et al. 2017). Alizarin red staining was used to determine the degree of mineralization in culture. Additional culture controls were completed with alpha-MEM (supplemented with 15% fetal bovine serum, 0.5% gentamycin, 10 mg/mL; Gibco) standard passaging media in combination with TAM receptor inhibitors. At 21 d, cells were harvested in RLT buffer and the RNA isolated (Qiagen RNEasy Kit) for RNA sequencing (RNAseq).

RNA Sequencing

RNAseq was performed by the University of Michigan Advanced Genomics Core using a NovaSeq 400 (Illumina). Reads were trimmed with Cutadapt (version 2.3; Martin 2011). Data quality was ensured via FastQC (version 0.11.8; Andrews 2010). FASTQ was used to screen for contamination (Wingett and Andrews 2018). Reads were mapped to the GRCm38 genome (Mertk ^–/– mouse data) or the GRCh38 genome (human alveolar bone MSC data) with STAR (version 2.8.8a; Dobin et al. 2013). Differential analysis was performed with DEseq2 (Love et al. 2014). Gene ontology was performed via Metascape (Zhou et al. 2019).

Statistical Analysis

Statistical analyses were performed in multiple comparisons by 1-way analysis of variance, followed by a Dunnett multiple-comparisons test, and single comparisons by t test analysis with Prism version 9.0.0 for Windows (GraphPad). P < 0.05 was used to delineate significance. Power analysis was conducted prior to all animal experiments.

Results

TAM Inhibition Accelerated Alveolar Bone Healing

We first tested the effects of inhibiting TAM receptor signaling on bone healing following tooth extraction (Fig. 1). We used the pan-TAM inhibitor RXDX-106 for these experiments, as triple-knockout mice are difficult to breed (Lu et al. 1999) and ligand-deficient mice (e.g., GAS6 ^–/– mice) do not lose signaling through all 3 TAM receptors (Lemke and Rothlin 2008). RXDX-106 was administered daily starting at the time of extraction for 7 d, at which we analyzed explanted maxillae for bone fill and histologic characteristics of the extraction socket (Fig. 1A). We visually observed increased bone fill in the extraction sockets of RXDX-106–treated mice as compared with vehicle-treated control mice (Fig. 1B–E). Hematoxylin and eosin staining of extraction sockets showed morphologically similar regenerated bone between vehicle- and RXDX-106–treated mice (Fig. 1B, C). Trichrome staining of vehicle- and RXDX-106–treated sagittal sections of extraction sockets showed morphologically similar sockets with noticeably more collagen staining in the sockets of RXDX-106–treated mice (Fig 1D, E). Visual inspection of μCT images of these same extraction sockets showed a corresponding increase in mineralization in RXDX-106–treated mice (Fig. 1F). Corresponding quantitative analysis of extraction sockets from vehicle- and RXDX-106–treated mice showed a 35% increase in bone volume:total volume ratio (percentage bone volume) in RXDX-106–treated mice (P < 0.01; Fig. 1G). We did not observe any changes in trabecular spacing (Fig. 1H), trabecular number (Fig. 1I), trabecular thickness (Fig. 1J), or connective density (Fig. 1K), indicating that the morphology of regenerated bone was similar in the 2 conditions.

TAM Inhibition Does Not Change Immune Dynamics After Extraction

We next examined the immunologic profile of extraction sockets 7 d postextraction in vehicle- and RXDX-106–treated mice (Fig. 2). TAM receptor signaling has been reported to play a significant role in the immune system (Lemke and Rothlin 2008), specifically in the clearance of apoptotic cells (Lemke and Burstyn-Cohen 2010); therefore, we hypothesized that an increased amount of immune infiltrate may be present in TAM inhibitor–treated extraction sockets. We measured populations of cells that were B220⁺ Cd11b^– (B cells), CD11b⁺ Ly6C-high Ly6G^– (monocytes), CD11b⁺ Ly6C-intermediate Ly6G⁺ (neutrophils), CD8⁺ (CD8 T cells), or CD4⁺ (CD4 T cells; Fig. 2A). Analysis of immune cell numbers in the extraction sockets of vehicle- and RXDX-106–treated mice by flow cytometry showed no difference in the number of immune cells (Fig. 2B) or B cells (Fig. 2C), monocytes (Fig. 2D), neutrophils (Fig. 2E), CD4⁺ T cells (Fig. 2F), or CD8⁺ T cells (Fig. 2G) between the conditions. These results indicated that chemical inhibition of TAM signaling did not alter the number of major immune cell populations in the extraction socket after extraction. Immunohistochemistry of extraction sockets for macrophage phenotypes found iNOS⁺ and CD206⁺ macrophages in vehicle- and RXDX-106–treated mice, indicating that inflammatory and anti-inflammatory macrophages are present in both treatment groups (Fig. 2H).

TAM Inhibition Promotes Osteogenic Differentiation of Alveolar Bone MSCs

Given that the impact of TAM inhibition on immune populations was not observed, we next sought to identify the phenotypic effects of TAM inhibition on the ability of MSCs to differentiate into matrix-producing osteoblasts (Fig. 3). To determine if TAM inhibition upregulated pathways that may prime stem cells toward the osteoblastic lineage, we treated cultures of primary human alveolar bone MSCs with RXDX-106 and performed RNAseq (Fig. 3A, Appendix Table 1). Gene ontology of the top 50 most strongly upregulated transcripts by RXDX-106 showed enrichment of transcripts involved in skeletal system development (GO:0001501) and chondrocyte differentiation (GO:0002062), with positive regulation of the Wnt signaling pathway as a common denominator (GO:0030177). We confirmed upregulation of the Wnt signaling pathway with a β-catenin transcription factor activity assay (Fig. 3B). Daily monitoring of β-catenin in alveolar bone MSCs treated for 12 to 14 d with RXDX-106 induced a 4-fold increase in relative activity as compared with vehicle-treated control cultures (Fig. 3B).

We next sought to identify the specific contributions of the different TAM receptors, specifically Axl and Mertk, on differentiation of alveolar bone MSCs. We treated cultures of alveolar bone MSCs with osteoblast differentiation media and one of either vehicle or the TAM-targeted inhibitor RXDX-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific). Tyro3 is not expressed on alveolar bone MSCs, and no specific inhibitor exists for this receptor. Alveolar bone MSC cultures treated with differentiation media produced significant amounts of calcified matrix as measured by alizarin red staining (Fig. 3C). Treatment with the pan-TAM inhibitor RXDX-106 and the Mertk-specific inhibitor MRX-2843 resulted in an increase in alizarin red–stained area relative to vehicle-treated control, while treatment with the AXL-specific inhibitor ASP-2215 decreased the stained area (Fig. 3C). Quantification of these images for alizarin red–stained area confirmed these changes (Fig. 3D). Treatment with the pan-TAM inhibitor RXDX-106 led to a 72% increase in stained area as compared with vehicle control (P < 0.05), while treatment with the Mertk inhibitor MRX-2843 led to a 131% increase in stained area (P < 0.0001). Treatment with ASP-2215 did not alter the stained area relative to the control (Fig. 3C).

Mertk ^–/– Mice Have Accelerated Bone Fill Following Extraction

We wanted to determine if inhibition of Mertk inhibition would enhance bone healing after extraction outside the context of small molecule inhibition. We therefore compared the healing of extraction sockets of wild type (WT) and Mertk^–/– C57BL6/j mice (Fig. 4A). We observed significantly increased bone fill 7 d postextraction histologically (Fig. 4B–E) and through μCT of the extraction sockets relative to WT controls (Fig. 4F). Mertk^–/– mice had a 36% increase in percentage bone volume in the extraction socket as compared with WT controls 7 d postextraction (P < 0.01; Fig. 4G). Mertk^–/– extraction sockets had decreased trabecular spacing (53% decrease, P < 0.05; Fig. 4H), no change in trabecular number (Fig. 4I), decreased trabecular thickness (22% decrease, P < 0.01; Fig. 4J), and increased connective density (Fig. 4K), indicating altered morphology of regenerating bone in the Mertk^–/– mice.

We wanted to identify a potential mechanism through which Mertk ^–/– mice had enhanced bone fill after extraction. Flow cytometry found no differences in immune cell counts in day 7 extraction sockets between WT and Mertk^–/– mice (Fig. 4L), similar to the results for pan-TAM inhibition (Fig. 2). We also observed CD206⁺ and iNOS⁺ macrophages in the extraction sockets of Mertk^–/– mice (Fig. 4M). RNAseq of day 7 extraction sockets showed significant differences between Mertk ^–/– and WT extraction sockets (Fig. 5A, Appendix Table 2). Highly upregulated genes in Mertk^–/– extraction sockets include innate immune markers such as Cd14, Ccr1, Cxcl1, and Tnf (Fig. 5A). Gene ontology of upregulated genes in Mertk^–/– extraction sockets showed enrichment for inflammatory pathways (GO:0006954, GO:0002526) as well as associated pathways (e.g., JAK-STAT signaling, mmu04630; Fig. 5B). The strongest upregulated set of genes in WT extraction sockets as compared with Mertk^–/– extraction sockets was that regulating neutrophil degranulation (R-MMU-6798695) and production of antimicrobial peptides (Fig. 5C). Comparison of known markers for bone differentiation found Jag1, Spp1, Tbx21, and Runx2 as upregulated in Mertk^–/– extraction sockets, while Sp7, Col1a1, Alpl, and Bglap were upregulated in WT extraction sockets (Fig 5D). Notably, pathways associated with bone formation or turnover were absent in the gene sets associated with Mertk ^–/– and WT, indicating that the signaling within the extraction sockets was dominated by innate immune-signaling events.

Discussion

Different activities have been attributed to TAM receptor signaling and binding to their ligands Gas6 and Pros1, including cell growth, macrophage efferocytosis, and resolution of the inflammatory wound-healing phase (Sainaghi et al. 2021). An increased presence of TAM receptors has also been recently observed in the progression of inflammatory disorders (Bellan et al. 2019). One unique feature of the TAM receptors includes proteolytic cleavage of their extracellular domain to render a soluble form of the receptor (sTAM), which has been reported with sAXL and sMER, though the functions of these soluble receptors are poorly understood (Thorp et al. 2011). These soluble receptors (as well as Gas6) have been evaluated recently as biomarkers of disease severity in many chronic inflammatory disorders, including systemic lupus erythematosus (Ballantine et al. 2015), rheumatoid arthritis (Xu et al. 2018), sepsis (Salmi et al. 2019), and liver cirrhosis (Smirne et al. 2019). Our experiments provide evidence for a new function of TAM receptor signaling in promoting the healing of alveolar bone (Fig. 1), through acting directly on MSCs (Figs. 3 and 4) as well as indirectly through modulation of innate immune functions (Fig. 5).

Our flow cytometry experiments indicated that treatment of mice with a pan-TAM inhibitor did not alter immune infiltrate (Fig. 2) yet did improve mineralization of differentiated MSCs in vitro (Fig. 3). RNAseq and transcription factor activity measurements of MSCs treated with pan-TAM inhibitor suggested that these cells may become primed to differentiate down the osteoblastic lineage through upregulation of Wnt signaling. Wnt signaling through β-catenin has been shown to be essential for skeletal development (Hartmann 2006). TAM signaling canonically proceeds through PI3K and AKT (Linger et al. 2008), which converges with Wnt signaling through GSK3β and β-catenin. These pathways have convergent signaling mediators and have been shown to be complementary in cancer models (Arqués et al. 2016). Importantly, activation of PI3K-Akt in MSCs has been shown to promote differentiation toward the adipogenic lineage by activating mTOR (Chen et al. 2013), which is suppressive to Wnt signaling (Zeng et al. 2018). These results suggest a molecular mechanism through which TAM inhibition enhances bone differentiation and potential adjuvants to enhance this effect. Possible synergistic effects of TAM inhibition may also be relevant for tissue engineering. Pairing of TAM inhibition with engineered scaffolds with previously studied extracellular matrix proteins (e.g., periostin) that promote Wnt activation may enhance bone formation after injury (Barakzai et al. 2023).

Our experiments targeting specific receptors indicated that Mertk was a therapeutic target for bone regeneration, while inhibition of Axl may inhibit the formation of new bone following extraction (Figs. 3 and 4). Axl is overexpressed in many bone metastatic cancers, including breast cancer and prostate cancer (Decker et al. 2017; Tanaka et al. 2021). In osteoclast progenitor cells, genetic and pharmacologic inhibition of Axl inhibited osteoclast maturation and differentiation (Tanaka et al. 2021). It is possible that inhibition of Axl results in cell-cycle arrest in MSCs and osteoblasts and thereby inhibits their ability to form new bone, while inhibition of Mertk targets different pathways and types of cells without inducing cell-cycle arrest. RNAseq of Mertk^–/– extraction sockets indicated a differential innate immune phenotype in these mice relative to WT mice in response to extraction, despite having similar numbers of innate immune cells, supporting this hypothesis (Fig. 5).

It is well established that TAM receptors are involved in immune processes, as evident from the increased susceptibility of Mertk ^–/– mice to lipopolysaccharide-induced inflammation (Camenisch et al. 1999) and TAM receptor triple-knockout mice displaying autoimmune features (Lu and Lemke 2001). The response of the TAM receptors appears to be cell type/situation dependent, as congruent as well as opposing responses have been reported. For example, Axl and Mertk have been shown to work in concert for optimal clearance of apoptotic cell bodies by bone marrow–derived macrophages (Zagórska et al. 2014) and microglia (Fourgeaud et al. 2016). However, Axl and Mertk may have also showed opposing action regarding support of an inflammatory microenvironment, with Mertk expression increasing with anti-inflammatory–biased cytokine responses and Axl expression increasing the inflammatory-biased cytokine profile (Healy et al. 2016).

The experiments in this work suggest a new therapeutic target, Mertk, in alveolar bone healing. TAM receptor inhibition led to activation of bone differentiation pathways in MSCs, while Mertk deficiency appeared to change innate immune phenotypes after extraction to promote alveolar bone healing. Future experiments using cell type–specific deficiency of Mertk will elucidate the mechanisms through which this pathway affects alveolar bone healing and what, if any, effect Mertk inhibition may have on regenerated bone quality. Furthermore, we chose to focus on an early time point for these studies, which primarily involves initial immune signaling from damage-associated molecular patterns and lineage commitment from resident MSCs. Future studies focusing on the role of Mertk on bone turnover and maturation during later time points will strengthen the case for using this receptor as a therapeutic target and inform possible clinical applications of Mertk inhibitors for alveolar bone regeneration.

Author Contributions

A.M. Decker, contributed to conception and design, data acquisition, analysis, and interpretation, drafted and critically revised manuscript; M. Matsumoto, J.T. Decker, contributed to data acquisition, analysis, and interpretation, critically revised the manuscript; A. Roh, J. Sugai, contributed to data acquisition, critically revised the manuscript; N. Inohara, contributed to data analysis, critically revised the manuscript; K. Martin, contributed to acquisition, critically revised the manuscript; R. Taichman, D. Kaigler, L.D. Shea, contributed to data conception and design, critically revised the manuscript; G. Núñez, contributed to data conception and design, drafted and critically revised the manuscript. All authors gave their final approval and agreed to be accountable for all aspects of the work.

Supplemental Material

sj-docx-1-jdr-10.1177_00220345231177996 – Supplemental material for Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction

Supplemental material, sj-docx-1-jdr-10.1177_00220345231177996 for Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction by A.M. Decker, M. Matsumoto, J.T. Decker, A. Roh, N. Inohara, J. Sugai, K. Martin, R. Taichman, D. Kaigler, L.D. Shea and G. Núñez in Journal of Dental Research

Footnotes

A supplemental appendix to this article is available online.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by National Institute of Dental and Craniofacial Research grants K99/R00DE029756 (A.M.D.), R01DE028657 (D.K.), and P01CA093900 (R.T.). The funders had no role in the design, analysis, or reporting of this study. Data availability

RNAseq data were deposited in the National Institutes of Health Gene Expression Omnibus, accession GSE223778.

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Supplementary Material

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Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction

Abstract

Keywords

Introduction

Materials and Methods

Animals

Flow Cytometry Analysis

Micro–computed Tomography

Histology

In Vitro Osteoblast Differentiation

RNA Sequencing

Statistical Analysis

Results

TAM Inhibition Accelerated Alveolar Bone Healing

TAM Inhibition Does Not Change Immune Dynamics After Extraction

TAM Inhibition Promotes Osteogenic Differentiation of Alveolar Bone MSCs

Mertk –/– Mice Have Accelerated Bone Fill Following Extraction

Discussion

Author Contributions

Supplemental Material

sj-docx-1-jdr-10.1177_00220345231177996 – Supplemental material for Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction

Footnotes

Declaration of Conflicting Interests

Funding

References

Supplementary Material

Mertk ^–/– Mice Have Accelerated Bone Fill Following Extraction