The Role of Pericyte Migration and Osteogenesis in Periodontitis

Abstract

A ligature-induced periodontitis model was established in wild-type and CD146^CreERT2; Rosa^tdTomato mice to explore the function of pericytes in alveolar bone formation. We found that during periodontitis progression and periodontal wound healing, CD146⁺/NG2⁺ pericytes were enriched in the periodontal tissue areas, which could migrate to the alveolar bone surface and colocalize with ALP⁺/OCN⁺ osteoblasts. Chemokine C-X-C motif receptor 4 (CXCR4) inhibition using AMD3100 blocked CD146-Cre⁺ pericyte migration and osteogenesis, as well as further exacerbated periodontitis-associated bone loss. Next, primary pericytes were sorted out by magnetic-activated cell sorting and demonstrated that C-X-C motif chemokine ligand 12 (CXCL12) promotes pericyte migration and osteogenesis via CXCL12-CXCR4-Rac1 signaling. Finally, the local administration of an adeno-associated virus for Rac1 overexpression in NG2⁺ pericytes promotes osteoblast differentiation of pericytes and increases alveolar bone volume in periodontitis. Thus, our results provided the evidence that pericytes may migrate and osteogenesis via the CXCL12-CXCR4-Rac1 axis during the pathological process of periodontitis.

Keywords

bone biology bone remodeling/regeneration cell signaling inflammation osteoblast(s)stem cell(s)

Introduction

Periodontitis (PD) is a chronic multifactorial inflammatory disease associated with dysbiotic plaque biofilms and characterized by progressive destruction of the tooth-supporting apparatus. Periodontitis is one of the most common and complicated oral diseases, affecting 20% to 50% of the worldwide population (Nazir 2017). Although scaling and root planning are effective methods for preventing the progression of periodontitis, these methods cannot recover lost alveolar bone (Xu et al. 2019).

Recent advances in generative medicine by mesenchymal stem cells (MSCs) have paved the way to improve bone regeneration. Nevertheless, a single-cell sequencing study found that periodontitis leads to a sharp decrease in the number of MSCs and osteoblasts (OBs) (Chen et al. 2022). Therefore, is there a substitute for MSCs in periodontal tissues to promote the regeneration of alveolar bone? Recent data from our group have indicated that the population of pericytes is increased significantly in patients with chronic periodontitis (Chen et al. 2022). Pericytes are defined as the cells that surround the endothelial cells of blood vessels (Harrell et al. 2018). CD31 is the marker of endothelial cells, while pericytes can be identified by CD146 (Wang et al. 2019) or NG2 (Lin et al. 2008). Functionally, pericytes not only contribute to the stabilization and maturation of blood vessels (Bergers and Song 2005) but also possess multilineage differentiation potential, including osteogenic, adipogenic, and chondrogenic differentiation capabilities (Herrmann et al. 2016; Supakul et al. 2019). However, the precise role of pericytes in periodontitis progression and periodontal wound healing remains unclear.

It was reported that C-X-C motif chemokine ligand 12 (CXCL12)⁺ MSC-like pericytes could convert their identity into a preosteoblast state during inflammatory responses even after initial periodontal therapy (Chen et al. 2022). Multiple studies suggest that CXCL12 plays a critical role in bone homeostasis (Castillo and Leucht 2015; Yin et al. 2019), fracture repairing (Edderkaoui 2017), and defects healing (Zhang et al. 2017). CXCL12 was also found highly expressed in the regions that would potentially develop pathological new bone. Osteogenic precursor cells were recruited to these regions where CXCL12 was upregulated (Cui et al. 2022). In addition, CXCL12 encoded protein functions as the ligand for the G-protein coupled receptor, chemokine C-X-C motif receptor 4 (CXCR4). It was observed that CXCR4⁺ pericytes represent an osteogenic cell precursor (Xu et al. 2020). Moreover, CXCL12-CXCR4 interplay facilitates osteogenesis in mice (Verheijen et al. 2020). However, the effects of CXCL12-CXCR4 interaction on pericyte migration and osteogenesis in the periodontal inflammatory microenvironment are less clear.

The current study seeks to elucidate the role of pericyte in the process of periodontitis progression and periodontal wound healing. We used the classic ligature-induced periodontitis model in both wild-type (WT) mice and CD146^CreERT2; Rosa^tdTomato mice. By using this model, periodontitis can be triggered at a specific time (Abe and Hajishengallis 2013) and be partially rescued within a few days after removing the ligature (Wong et al. 2018; Lin et al. 2021). Thereby, we compared the changes of periodontal pericytes during periodontitis progression and recovery from inflammation. In addition, we performed a series of migration- and osteogenesis-related experiments using pericytes to explore the corresponding mechanism.

Materials and Methods

Animals

CD146^CreERT2; Rosa^tdTomato mice were obtained by crossing CD146^CreERT2 mice with Rosa^tdTomato mice. CD146^CreERT2; Rosa^tdTomato mice were used to trace CD146 linage cells in periodontal tissue after periodontitis onset. In CD146^CreERT2; Rosa^tdTomato mice, all CD146-Cre⁺ pericytes and their descendants in periodontal tissue express tdTomato. Cre-recombinase activity was induced by delivery of a solution of tamoxifen (cat. T5648; Sigma-Aldrich) in corn oil. Tamoxifen was injected at 6 wk intraperitoneally 80 mg/kg/d during 5 consecutive days. AMD3100 (cat. HY-10046; MCE) or phosphate-buffered saline (PBS) was injected intraperitoneally to mice (5 mg/kg/d) thereafter for 14 d. For induction of periodontitis, a 5-0 silk ligature was placed in the submarginal position on the left maxillary first molar and the contralateral tooth was left unligated to serve as the baseline control. Mice were sacrificed and analyzed 7 d (PD 7d) or 14 d (PD 14d) after placement of the ligature. Furthermore, the ligature was placed around the maxillary first molar and removed 7 d thereafter, creating the ligature-removed group (PDT 7d). Mice were sacrificed and analyzed 14 d after placement of the ligature. All mice were bred and maintained in the SPF Laboratory Animal Center of Nanjing Medical University. All animal procedures were conducted in accordance with approved guidelines of the Committee of Nanjing Medical University for Animal Resources (Approval ID 1906018).

Additional information may be found in the Appendix Materials and Methods. Our study design complied with ARRIVE (Animal Research: Reporting of In Vivo Experiments) 2.0 guidelines.

Results

Increased Pericytes during Periodontitis Progression and Periodontal Wound Healing

To examine the role of pericytes in the pathological and healing processes of periodontitis, a ligature-induced periodontitis model was used. Alveolar bone volume by micro–computed tomography (CT) analysis was decreased, whereas the distance from the cemento-enamel junction (CEJ) to the alveolar bone crest (ABC), the tartrate-resistant acid phosphatase (TRAP)–positive osteoclast surface, and the alkaline phosphatase (ALP)–positive osteoblast surface were increased in the PD 7d group compared with that in sham group (Fig. 1A–D). Furthermore, all the parameters deteriorated in the PD 14d group but improved in the PDT 7d group compared with that in the PD 7d group (Fig. 1A–D).

By immunofluorescence (IF) staining, we observed numerous CD31⁺ endothelial cells and CD146⁺ pericytes in periodontal tissues in PD 7d, PD 14d, and PDT 7d group compared with that in the sham group (Fig. 1E, F). To more specific identify pericytes, paraffin-embedded tissue sections were double-stained with anti-CD146 and anti-NG2 antibodies. Similarly, there were many more CD146⁺NG2⁺ pericytes in periodontal tissues during periodontitis progression and periodontal wound healing (Fig. 1G, H). Interestingly, although the number of CD146⁺NG2⁺ pericytes in periodontal tissues was decreased in the PDT 7d group, the number of CD146⁺NG2⁺ pericytes on the bone surface was almost the same (Fig. 1G, H). Therefore, CD146⁺NG2⁺ pericytes were more adjacent to the alveolar bone surface in the periodontal wound-healing process. Taken together, these data revealed that pericytes enrich in the periodontal tissues during periodontitis progression and periodontal wound healing. Moreover, pericytes might migrate from the blood vessel to the alveolar bone surface during recovery from periodontitis.

Pericytes That Differentiate into Osteoblasts Have an Intimate Relationship with CXCR4 in Periodontitis

To gain more insight into the role of pericytes during bone recovery in periodontitis, paraffin-embedded tissue sections of 2-mo-old WT mice were stained with anti-CD146/anti-NG2 antibodies for pericytes and anti-ALP/anti-OCN antibodies for osteoblasts. As shown in Figure 1E–H, we detected numerous CD146⁺ or NG2⁺ pericytes that were located adjacent to the alveolar bone surface during periodontitis progression and periodontal wound healing. Importantly, these CD146⁺ or NG2⁺ pericytes could colocalize with ALP⁺ or OCN⁺ osteoblasts. The number of CD146⁺ALP⁺ cells or NG2⁺OCN⁺ cells per millimeter bone parameter was significantly increased in the PD 7d, PD 14d, and PDT 7d groups compared with that in the sham group (Fig. 2A, Appendix Fig. 1). In addition, CD146^CreERT2; Rosa^tdTomato mice were used to explore the role of CD146 linage pericytes in the periodontal tissues after periodontitis onset. We found a few CD146-Cre⁺ pericytes located in the periodontal tissues of the sham group. Nevertheless, in the PD group, numerous CD146-Cre⁺ pericytes migrated to the alveolar bone surface and were colocalized with OCN⁺ osteoblasts, suggesting pericytes may take part in the osteogenic process (Fig. 2B).

We next set out to determine the mechanism responsible for pericyte migration and osteogenesis. Paraffin-embedded tissue sections were double-stained with anti-CD146 and anti-CXCR4 antibodies. CD146⁺CXCR4⁺ pericytes numbers were remarkably increased in the PD 7d, PD 14d, and PDT 7d groups compared with that in the sham group. Although CD146⁺ CXCR4⁺ pericyte numbers were decreased in the PD 14d and PDT 7d groups compared with that in PD 7d group, the number of the CD146⁺CXCR4⁺ pericytes located adjacent to the alveolar bone surface was almost the same (Fig. 2C). These data suggested that CXCR4 might function as a critical role in the process of pericyte migration and osteogenesis.

To explore the role of CXCR4 in pericyte migration and osteogenesis, CD146^CreERT2; Rosa^tdTomato mice were administered with AMD3100, a CXCR4 specific inhibitor. We found CD146-Cre⁺OCN⁺ cells per millimeter bone parameter were increased in the PD group compared with that in the sham group, which was blocked by AMD3100 treatment, as indicated by ligature-induced PD mice receiving AMD3100 compared with that receiving PBS (Fig. 2D). Furthermore, alveolar bone volume by micro-CT and hematoxylin and eosin (H&E) staining was decreased (Fig. 2E, Appendix Fig. 2A), whereas TRAP-positive osteoclast surface was increased (Appendix Fig. 2B) in the ligature-induced PD group compared with the sham group. Importantly, alveolar bone volume was decreased in ligature-induced PD mice receiving AMD3100 compared with that receiving PBS (Fig. 2E, Appendix Fig. 2A). Taken together, these data suggested that CXCR4 functions as an important role in pericyte migration and osteogenesis.

Pericytes Migrate via CXCL12-CXCR4 Signaling

To explore the role of CXCR4 in pericyte migration, pericytes were sorted out by magnetic-activated cell sorting (MACS) (Supakul et al. 2019). Following purification, flow cytometry was performed to demonstrate that about 95% cells were CD45.2^–CD31^–TER119^–NG2⁺ pericytes (Fig. 3A, B). Next, immunocytochemistry staining was used to examine the isolated cells. The percentage of CD146⁺CXCR4⁺ and NG2⁺CXCR4⁺ areas was increased clearly after isolation (Fig. 3C, D).

To further determine the effects of CXCR4 activation or inhibition on pericyte migration, pericytes were exposed to CXCL12 and/or AMD3100 during growth and migration. Transwell migration assay and scratch migration assay were used to examine the vertical migration and lateral migration capacities of pericytes, respectively. Results showed that both parameters were increased in CXCL12-treated groups but decreased in AMD3100-treated groups compared with that in vehicle-treated groups, as measured by migrated cells and relative scratch width (Fig. 3E, F). Furthermore, the increased migration ability by CXCL12 treatment could be partially blocked by AMD3100 treatment (Fig. 3E, F). Taken together, these data suggested that pericytes might migrate via CXCL12-CXCR4 signaling.

Pericytes Differentiate into Osteoblasts via CXC12-CXCR4-Rac1 Signaling

To further determine the mechanism responsible for CXCR4-mediated pericyte osteoblastogenesis, pericytes were exposed to CXCL12 ± LPS ± AMD3100 during osteoblast induction. We found that CXCL12 promoted pericyte differentiation into osteoblasts in a dose-dependent manner, as measured by the percentage of ALP⁺ area (Fig. 4A). The expression level of ALP was significantly decreased in the LPS-primed group compared with vehicle-treated group. Moreover, CXCL12-treated pericytes formed more osteoblasts and expressed higher levels of ALP. Importantly, LPS-treated pericytes formed more ALP⁺ osteoblasts in the presence of CXCL12 (Fig. 4B). In contrast, the increased osteoblastogenesis caused by CXCL12 could be partially blocked by AMD3100 treatment (Fig. 4C). Similarly, the percentage of OCN- and SP7-positive areas was increased in the CXCL12-treated group and reduced in the AMD3100-treated group but not significantly altered in the CXCL12 plus AMD3100-treated group relative to vehicle-treated group (Fig. 4D).

Downstream of CXCR4 is the Rho-GTPase family, which mainly consists of the 3 most important characteristic members, which are RHOA, Rac1, and CDC42 (Wherlock and Mellor 2002; Cho et al. 2004; Cui et al. 2022). To gain insight into the mechanism of pericyte osteogenesis, pericytes were exposed to CXCL12 and AMD3100 during osteoblast differentiation to examine the changes of CXCR4-mediated signaling pathway. By Western blot analysis, the expression levels of CDC42 and RHOA were unchanged in CXCL12 ± AMD3100-treated pericytes. In contrast, the expression level of Rac1 was increased in the CXCL12-treated group and reduced in the AMD3100-treated group but not significantly altered in the CXCL12 plus AMD3100-treated group relative to vehicle-treated group (Fig. 4E). Furthermore, the expression levels of p-MEK and p-ERK were increased in the CXCL12-treated group and reduced in the AMD3100-treated group but not significantly altered in the CXCL12 plus AMD3100-treated group relative to the vehicle-treated group (Fig. 4F). We next assessed the changes of osteoblast differentiation after CXCL12-CXCR4-Rac1 axis activation. The osteoblastic-related protein expression, including RUNX2, SP7, ALP, OPN and BMP2, was increased in the CXCL12-treated group and decreased in the AMD3100-treated group but not significantly altered in the CXCL12 plus AMD3100-treated group relative to the vehicle-treated group (Fig. 4G). These data were further confirmed by immunocytochemistry staining. The percentage of the NG2⁺Rac1⁺ area was increased in the CXCL12-treated group and reduced in the AMD3100-treated group but not significantly changed in the CXCL12 plus AMD3100-treated group relative to the vehicle-treated group (Fig. 4H). These data indicated that Rac1 may be the crucial member of the Rho-GTPase family that mediates CXCL12/CXCR4-induced osteoblast differentiation of pericytes.

Rac1 Overexpression Enhances the Osteogenesis of Pericytes in Periodontitis

To determine if overexpressed Rac1 promotes pericyte osteogenesis in periodontitis, a recombinant adeno-associated virus (AAV) encoding a full-length mouse Rac1 cDNA under a NG2-promoter (Coucha et al. 2019) was used. Two-month-old WT mice were administered a single injection of AAV-Rac1 virus or control AAV-GFP virus into the periodontal tissues of the maxillary first molar (Wang et al. 2020). The successful construction of the AAV-Rac1 virus was confirmed by IF staining for NG2. GFP signals were found to be merged with NG2⁺ pericytes (Fig. 5A), which suggested the successful construction of AAV with the targeted overexpression of Rac1 in pericytes.

We next set out to explore the effect of Rac1 overexpression on pericyte osteogenesis. We observed that GFP⁺OCN⁺ or GFP⁺ALP⁺ cells per millimeter bone parameter were increased in the ligature-induced PD7 group compared with the sham group, which was even higher after AAV-Rac1 treatment, as indicated by ligature-induced PD7 mice receiving AAV-Rac1 compared with that receiving AAV-GFP (Fig. 5B, C). With these results, we further investigated the changes of bone formation in periodontitis after AAV-Rac1 treatment. Alveolar bone volume was decreased (Fig. 5D, E), whereas TRAP-positive osteoclast surface was increased (Fig. 5F) in the ligature-induced PD7 group compared with the sham group in mice receiving AAV-GFP. Importantly, alveolar bone volume was increased in ligature-induced PD7 mice receiving AAV-Rac1 compared with that receiving AAV-GFP (Fig. 5D, E). Taken together, these data suggested that Rac1 overexpression enhances pericyte osteogenesis in periodontitis.

Discussion

The main findings of the present study are as follows: 1) Pericytes are evidently increased and could differentiate into osteoblasts during periodontitis progression and periodontal wound healing. 2) CXCL12 promotes pericyte migration and osteogenesis via CXCL12-CXCR4-Rac1 signaling in periodontitis-associated bone loss.

A lot of explorations have been made to seek methods for promoting clinical bone regeneration in periodontitis, especially how to use MSCs to promote alveolar bone recovery. However, it was observed that the fractions of MSCs in the periodontal tissues are significantly decreased in periodontitis (Chen et al. 2022). Thus, it is very meaningful to find superior alternative cells in the periodontal tissues. Our present study found that pericytes not only could differentiate into osteoblasts but also were evidently increased during both the pathological and healing processes of periodontitis. Therefore, pericytes may serve as a superior candidate to recover lost alveolar bone in periodontitis. However, what is the relationship between MSCs and pericytes? Are they the same cell type (Supakul et al. 2019)? Some studies have postulated that MSCs originate from pericytes (Crisan et al. 2008; Caporarello et al. 2019). Other scholars have speculated that pericytes derived from MSCs (Thomas et al. 2017; Tian et al. 2017). Despite the controversial relationship between MSCs and pericytes, it was observed that patients with periodontitis display decreased frequency of CD45⁻CD105⁺CD73⁺ MSCs compared with that of healthy controls (Chen et al. 2023), while our study found CD146⁺NG2⁺ pericytes were increased in periodontitis.

Pericytes were reported have the dual role of anti-inflammatory and proinflammatory in the regulation of inflammation. Some reported pericytes become activated by inflammatory mediators and then function to attenuate inflammation and promote tissue repair (Bodnar et al. 2018). Nevertheless, others argued that pericytes mediate leukocyte diapedesis and are related to inflammation infiltration (Dohgu et al. 2019). In this study, we found that pericytes promoted osteogenesis during the process of periodontitis. This observation hinted that pericytes may play multiple roles in periodontitis, and the specific mechanisms are ongoing investigations.

We used genetic lineage tracing to confirm that CD146⁺ pericytes migrate and differentiate into osteoblasts via CXCR4 in vivo. AMD3100, as a potent CXCR4 inhibitor, has been reported to suppress osteoblastic differentiation of pericytes (Xu et al. 2020). Correspondingly, our results confirmed that AMD3100 inhibited the migration and osteogenesis of pericytes. Although the effects were incomplete, given the fact that AMD3100 accelerated the destruction of the alveolar bone, it is possible that the decreased alveolar bone volume caused by AMD3100 may be partly due to the effects of AMD3100 on CXCR4 signal axis. The specific mechanisms may need further investigations.

Recent data from our group have indicated that CXCL12 expression is highly increased in periodontitis (Chen et al. 2022). In the present study, CXCL12 promoted migration and osteoblast differentiation of pericytes. Importantly, CXCL12 increased the LPS-induced lower osteoblastic capacity of pericytes, which suggested that CXCL12 may be a hopeful cytokine to treat periodontitis. Furthermore, our data indicated that Rac1 may mediate CXCL12/CXCR4-induced osteoblast differentiation of pericytes. However, CXCR4 is also expressed in nonpericytes such as hematopoietic and endothelial cells, neurons, and especially osteoblasts (Shahnazari et al. 2013). Thus, to avoid the direct effects of CXCL12 on osteoblasts, local injection of AAV-Rac1 with the targeted Rac1 overexpression in pericytes was used to achieve the activation of CXCL12-CXCR4-Rac1 signaling in vivo. Data revealed that Rac1 overexpression in pericytes enhanced pericyte osteogenesis and promoted alveolar bone recovery. Notably, although locally administrated AAV-Rac1 rescued alveolar bone volume, the effects were incomplete, indicating that either the concentration of Rac1 was insufficient or, more likely, other factors contribute to the alveolar bone recovery. It would be beneficial to generate pericyte-specific Rac1 overexpression or knockout mice by crossing Rac1 transgenic mice or Rac1^flox/flox mice with CD146-Cre mice and then perform ligature-induced periodontitis to investigate the role of Rac1 in pericyte osteogenesis.

Osteoblast–osteoclast coupling serves to balance the activity of the 2 cell types, ensuring equilibrium between bone production and bone resorption is maintained (Sims and Gooi 2008). Recent findings show that osteoclast differentiation is tightly regulated by osteoblasts through several different mechanisms (Kim et al. 2020). Furthermore, osteoblasts produce a range of secretory molecules that affect osteoclast differentiation (Chamoux et al. 2008). Indeed, Rac1 overexpression could promote pericytes to differentiate into osteoblasts. Since the coupling between osteoclast-mediated bone resorption and osteoblast-mediated bone formation is perturbed during persistent inflammation (Turner et al. 2018), more investigation is required to identify how Rac1 overexpression promotes osteoclast differentiation in the inflammatory milieu. Moreover, as for the ligature-induced periodontitis model, it was suggested that the time required for the occurrence of the chronic periodontitis in mice is generally 3 wk (Zhang et al. 2023), which hinted that our periodontitis mice were in an acute inflammatory state. Many studies have reported that appropriate acute inflammation response is favorable to osteogenesis (Gu et al. 2022). Therefore, we found more osteoblasts in the periodontitis groups compared to the sham group. The ligature-induced periodontitis model cannot completely represent all aspects of periodontitis in humans but is currently considered one of the most widely used models in periodontal research. Nevertheless, as human periodontitis is generally chronic inflammation, chronic periodontitis animal models are needed in a future study.

In the present study, we emphasize the key role of pericytes in promoting alveolar bone recovery in periodontitis. CXCL12 interacts with CXCR4, which results in the activation of CXCL12-CXCR4-Rac1 signaling, as well as promotes pericyte migration and osteogenesis in periodontitis. This study more profoundly shows the specific mechanism of pericyte-mediated osteoblastic bone formation, which might give us new hope in recovering the lost alveolar bone caused by periodontitis in the future.

Author Contributions

Y. Cao, Q. Ni, W. Sun, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript; C. Bao, H. Wang, contributed to data interpretation, critically revised the manuscript; C. Cai, T. Wang, X. Ruan, Y. Li, contributed to conception, design, data analysis and interpretation, critically revised the manuscript; R. Wang, contributed to conception, design, data acquisition, analysis, and interpretation, critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.

Supplemental Material

sj-docx-1-jdr-10.1177_00220345241244687 – Supplemental material for The Role of Pericyte Migration and Osteogenesis in Periodontitis

Supplemental material, sj-docx-1-jdr-10.1177_00220345241244687 for The Role of Pericyte Migration and Osteogenesis in Periodontitis by Y. Cao, Q. Ni, C. Bao, C. Cai, T. Wang, X. Ruan, Y. Li, H. Wang, R. Wang and W. Sun in Journal of Dental Research

Footnotes

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: The research was supported by grants from the National Natural Science Foundation of China (82071086), the Jiangsu Provincial Key R&D Programme (BE2023835), and the Project of Basic Science Research in Higher Education Institutions of Jiangsu Province (23KJA320002). This work was also supported by the Jiangsu Province Capability Improvement Project through Science, Technology and Education-Jiangsu Provincial Research Hospital Cultivation Unit (YJXYYJSDW4) and the Jiangsu Provincial Medical Innovation Center (CXZX202227).

ORCID iD

W. Sun

Data Availability

The authors declare that all data supporting the findings of this study are available within the article or are available from the corresponding author upon request.

A supplemental appendix to this article is available online.

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