Progranulin Promotes Regeneration of Inflammatory Periodontal Bone Defect in Rats via Anti-inflammation, Osteoclastogenic Inhibition, and Osteogenic Promotion

Abstract

Progranulin (PGRN) has been proved to play a crucial role in anti-inflammation and osteogenesis promotion; thus, it was hypothesized that PGRN could promote bone regeneration in periodontal disease. In this experiment, the periodontal bone defects were established in periodontitis rats; recombinant human progranulin (rhPGRN), tumor necrosis factor alpha inhibitor (anti-TNF-α), or phosphate buffer saline (PBS)-loaded collagen membrane scaffolds were implanted within defects and the rats were sacrificed at scheduled time points. Volume of new bone was assessed by radiological and histomorphometric analyses. Expression of osteogenesis-related markers and tumor necrosis factor-α (TNF-α) was evaluated using immunohistochemistry. Tartrate-resistant acid phosphatase (TRAP) staining was also performed to determine the number of osteoclasts. Immunofluorescence (IF) staining was performed to explore the interaction between rhPGRN and tumor necrosis factor receptors (TNFRs). The results showed that the rhPGRN group had significantly superior quantity and quality of newly formed bone, higher expression of alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and TNFR2 compared with the PBS group and the anti-TNF-α group. Similarly to the anti-TNF-α group, the rhPGRN group also exhibited the significant inhibitory effect on the expression of TNF-α and the number of TRAP-positive cells compared with the PBS group. Hence, our experiment suggests that PGRN promotes regeneration of inflammatory periodontal bone defect in rats via anti-inflammation, osteoclastogenic inhibition, and osteogenic promotion. Local administration of PGRN may provide a new therapeutic strategy for periodontal bone regeneration.

Progranulin promotes osteogenic differentiation of human periodontal ligament stem cells via tumor necrosis factor receptors to inhibit TNF‐α sensitized NF‐kB and activate ERK/JNK signaling

“…The result revealed that there was no significant difference in P65 expression between the TNF‐α and TNF‐α + PGRN stimulation groups in hPDLSCs‐sh‐TNFR1 (Figure C), whereas PGRN antagonized TNF‐α‐enhanced P65 expression in hPDLSCs‐NC (Figure B) and hPDLSCs‐sh‐TNFR2 (Figure D). These results as well as our previously revealed PGRN‐TNFR binding suggest that PGRN reverses TNF‐α‐mediated osteogenic inhibition through suppression of TNF‐α/TNFR1/NF‐κB signaling pathway.…”

“…PGRN competitively binds to TNFRs in hPDLSCs and is a natural antagonist of TNF‐α. In our study, we knocked down TNFR1 and TNFR2, respectively, to explore their role in PGRN‐mediated pro‐osteogenic differentiation.…”

“…However, anti‐inflammation and osteogenesis promotion by PGRN in periodontitis condition has been seldom investigated. Our recent studies indicated that PGRN was highly expressed in the gingiva and gingival crevicular fluid of patients with chronic periodontitis and exogenous PGRN could protect against experimental periodontitis in rats ; and PGRN could promote regeneration of inflammatory periodontal bone defect in rats via anti‐inflammation, osteoclastogenic inhibition, and osteogenic promotion . For deeper insight of the underlying mechanism of PGRN in improving periodontal regeneration, the present study was conducted to investigate the role of TNFR1 and TNFR2 as well as the underlying signaling pathways in the process of hPDLSCs osteogenic differentiation promoted by PGRN with or without TNF‐α stimulation.…”

EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation

“…Furthermore, various lines of evidence shows that PGRN-mediated anabolism of chondrocytes and bone formation depend on TNFR2 [34,35]. Moreover, TNFR2 activation plays a protective role in osteogenic differentiation and bone regeneration [3,4]. TNFR2 has been reported to play an important role in inflammation control, immune modulation, and neuronal protection.…”

EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation

“…The biological activities of TNF-α are mediated through two structurally distinct receptors, tumor necrosis factor receptor 1 (TNFR1) and TNFR2. In osteoblast precursor cells, TNFR1 mediates activation of NF-κB signaling and inhibition of osteogenic differentiation after TNF-α stimulation [2], whereas TNFR2 activation by progranulin (PGRN), a TNFR2 agonist, plays a protective role in osteogenic differentiation and bone regeneration [3,4]. Furthermore, TNF-α affects behaviors of mesenchymal stem cells (MSCs) and osteoblast precursor cells in a dose and time-dependent manner [2,5].…”