Abstract
The integrin-binding secreted protein developmental endothelial locus-1 (DEL-1) is involved in the regulation of both the initiation and resolution of inflammation in different diseases, including periodontitis, an oral disorder characterized by inflammatory bone loss. Here, using a mouse model of bone regeneration and in vitro cell-based mechanistic studies, we investigated whether and how DEL-1 can promote alveolar bone regeneration during resolution of experimental periodontitis. Compared with WT mice, mice lacking DEL-1 or expressing a DEL-1 variant with an Asp-to-Glu substitution in the RGD motif ("RGE point mutant"), which does not interact with RGD-dependent integrins, exhibited defective bone regeneration. Local administration of DEL-1 or of its N-terminal segment containing the integrin-binding RGD motif, but not of the RGE point mutant, reversed the defective bone regeneration in the DEL-1-deficient mice. Moreover, DEL-1 (but not the RGE point mutant) promoted osteogenic differentiation of MC3T3-E1 osteoprogenitor cells or of primary calvarial osteoblastic cells in a β3 integrin-dependent manner. The ability of DEL-1 to promote in vitro osteogenesis, indicated by induction of osteogenic genes such as the master transcription factor Runt-related transcription factor-2 (Runx2) and by mineralized nodule formation, depended on its capacity to induce the phosphorylation of focal adhesion kinase (FAK) and of extracellular signal-regulated kinase 1/2 (ERK1/2). We conclude that DEL-1 can activate a β3 integrin-FAK-ERK1/2-RUNX2 pathway in osteoprogenitors and promote new bone formation in mice. These findings suggest that DEL-1 may be therapeutically exploited to restore bone lost due to periodontitis and perhaps other osteolytic conditions.
Highlights
The integrin-binding secreted protein developmental endothelial locus-1 (DEL-1) is involved in the regulation of both the initiation and resolution of inflammation in different diseases, including periodontitis, an oral disorder characterized by inflammatory bone loss
Ligature placement simulates human periodontitis as it generates a subgingival biofilm-retentive milieu leading to dysbiotic inflammation and bone loss in conventional animals [14, 17, 18, 27,28,29,30,31,32,33,34]
We have shown that endogenous DEL-1 is required for effective bone regeneration during the resolution of experimental periodontitis
Summary
Dept. of Periodontology, School of Dentistry, National Defense Medical Center, Taipei 11490, Taiwan. Interaction of DEL-1 with the Mac-1 integrin on osteoclast precursors up-regulates the transcriptional repressor B cell lymphoma-6, which in turn inhibits the expression of the transcription factor nuclear factor of activated T cells-1 and osteoclast differentiation [14] The importance of these homeostatic functions of DEL-1 becomes phenotypically evident in DEL-1– deficient (Del1KO) mice in the setting of periodontitis, a prevalent inflammatory disease that affects the integrity of the tissues that surround and support the dentition, such as the gingiva and the underlying alveolar bone [15, 16]. The ability of DEL-1 to induce new bone formation in otherwise nonhealing mice suggests that DEL-1 may be exploited therapeutically to regenerate bone for the treatment of periodontitis and perhaps other bone loss disorders
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