Deficiency of the SMOC2 matricellular protein impairs bone healing and produces age-dependent bone loss

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.

Bevacizumab and sunitinib mediate osteogenic and pro-inflammatory molecular changes in primary human alveolar osteoblasts in vitro

“…Previous research indicated an involvement of MMPs in the development of MRONJ [ 59 ]. MMP1 cleaves interstitial collagens and digests other ECM molecules and soluble proteins [ 44 ].…”

Harnessing a Feasible and Versatile ex vivo Calvarial Suture 2-D Culture System to Study Suture Biology

“…Of relevance, Mest1 was the only gene with functional regulatory stemness property ( Hasegawa et al, 2020 ), identified from the analysis of genes downregulated in ex vivo skeletal stem/progenitor cells, and interestingly Copg2 a member of mouse imprinted genes linked to Mest1 was also downregulated ( Lee et al, 2000 ; Figure 5C ). Along with aforementioned, several genes encoding cell-adhesion proteins were also noticed, among them were Spon2 ( Zhang et al, 2018 ), Smoc2 ( Morkmued et al, 2020 ). Furthermore, SLR Immunoglobulin Superfamily Containing Leucine Rich Repeat ( Islr ), a secreted stromal protein promoting intestinal regeneration through inhibition of hippo signaling ( Xu et al, 2020 ) was also downregulated ( Figure 5C ).…”

Genome-Wide Association Study of Alzheimer’s Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery Dataset

“…The gene annotated to the associated region on chromosome 6q27, SMOC2 , encodes secreted modular calcium-binding protein 2. SMOC2 is an extracellular matrix protein from the secreted protein, acidic and rich in cysteine (SPARC) family ( Gao et al, 2019 ) recently linked to age-dependent bone loss in humans ( Morkmued et al, 2020 ). In the AD context, it is noteworthy that SMOC2 was recently found to be altered in CSF samples of early AD in a proteomics profiling study ( Whelan et al, 2019 ).…”