Discoidin Domain Receptor 2 Is Required for Tooth Extraction Socket Healing

Abstract

Discoidin Domain Receptor 2 (DDR2) is a collagen-activated tyrosine kinase required for bone and tooth development as well as regeneration of calvarial and long bones. Although DDR2 is expressed in alveolar bone, its functions in this site have not been previously examined. The present study used global and conditional knockout approaches and lineage tracing to examine the functions of DDR2 in alveolar bone formation during tooth socket healing. First molars were extracted from the maxillae of wild-type and globally Ddr2-deficient (Ddr2^LacZ/LacZ) mice, and socket healing was measured after 1, 2, or 4 wk. At all times, Ddr2 inactivation significantly reduced socket healing. These changes were associated with decreased cell proliferation 3 d after extraction without any detectable changes in apoptosis. In addition, collagen fibril orientation, measured using Picrosirius Red staining under polarized light, was disrupted in tooth sockets from Ddr2-deficient mice. For lineage tracing, 4-wk-old Ddr2^mer-cre-mer; R26R^tdTomato and Gli1^CreERT2; R26R^tdTomato mice were induced with tamoxifen, first molars were extracted, and socket healing was examined after 1, 3, or 7 d. In both cases, tdTomato+ cells migrated into sockets, where they sequentially co-localized with preosteoblast and osteoblast markers. Thus, both DDR2⁺ and GLI1⁺ cells contribute to socket healing. The considerable overlap observed between DDR2⁺ and GLI1+ cells suggested that DDR2 functioned in GLI1⁺ cells, which are known to have skeletal progenitor properties. Consistent with localization data, conditional knockout (Gli1^CreERT2; Ddr2^fl/fl) mice exhibited reductions in socket healing 1 wk postextraction, although the inhibition of socket repair was less than that seen in global Ddr2 knockouts. In summary, this work demonstrates a role for DDR2 in alveolar bone repair, a finding that may have therapeutic implications for the treatment of alveolar bone loss associated with periodontal disease and other disorders.