Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss
Supawich Morkmued, François Clauss, Brigitte Schuhbaur, Valérie Fraulob, Éric Mathieu, Joseph Hemmerlé, Hans Clevers, Bon‐Kyoung Koo, Pascal Dollé, Agnès Bloch‐Zupan, Karen Niederreither
Abstract
Abstract Secreted extracellular matrix components which regulate craniofacial development could be reactivated and play roles in adult wound healing. We report a patient with a loss-of-function of the secreted matricellular protein SMOC2 (SPARC related modular calcium binding 2) presenting severe oligodontia, microdontia, tooth root deficiencies, alveolar bone hypoplasia, and a range of skeletal malformations. Turning to a mouse model, Smoc2-GFP reporter expression indicates SMOC2 dynamically marks a range of dental and bone progenitors. While germline Smoc2 homozygous mutants are viable, tooth number anomalies, reduced tooth size, altered enamel prism patterning, and spontaneous age-induced periodontal bone and root loss are observed in this mouse model. Whole-genome RNA-sequencing analysis of embryonic day (E) 14.5 cap stage molars revealed reductions in early expressed enamel matrix components ( Odontogenic ameloblast-associated protein ) and dentin dysplasia targets ( Dentin matrix acidic phosphoprotein 1 ). We tested if like other matricellular proteins SMOC2 was required for regenerative repair. We found that the Smoc2-GFP reporter was reactivated in adjacent periodontal tissues 4 days after tooth avulsion injury. Following maxillary tooth injury, Smoc2 −/− mutants had increased osteoclast activity and bone resorption surrounding the extracted molar. Interestingly, a 10-day treatment with the cyclooxygenase 2 (COX2) inhibitor ibuprofen (30 mg/kg body weight) blocked tooth injury-induced bone loss in Smoc2 −/− mutants, reducing matrix metalloprotease (Mmp)9 . Collectively, our results indicate that endogenous SMOC2 blocks injury-induced jaw bone osteonecrosis and offsets age-induced periodontal decay.