Spatial and Temporal Localization of WNT Signaling Proteins in a Mouse Model of Distraction Osteogenesis

Abstract

While the surgical procedure of distraction osteogenesis (DO) is very successful in the treatment of orthopedic conditions, its major limitation of slow bone formation in the distracted gap has prompted numerous attempts to understand and accelerate this slow bone formation. Interestingly, WNT/FZD signaling has been identified as a critical pathway in mediating bone formation and regeneration but has not yet been studied in the context of DO. The objective of this study was to determine the spatial and temporal localization of endogenous WNT signaling proteins at various times of bone formation in a wild-type mouse model of DO. In this study, the DO protocol performed on mice consisted of three phases: latency (5 days), distraction (12 days), and consolidation (34 days). Our immunohistochemical findings of distracted bone specimens show an increased expression of WNT ligands (WNT4 and WNT10A), receptors (FZD1 and 2, LRP5 and 6), β-catenin, and pathway antagonizers (DKK1; CTBP1 and 2; sFRP1, 2, and 4) during the distraction phase, which were then down-regulated during consolidation. This is the first published report to show an activation of the WNT pathway in DO and could help identify WNT as a potential therapeutic target in accelerating bone regeneration during DO.

Fak‐Mapk, Hippo and Wnt signalling pathway expression and regulation in distraction osteogenesis

“…The results revealed that the Wnt pathway was more activated at the end of distraction, while the Hippo pathway was more activated during consolidation. These results were consistent with the previous studies, in which Wnt pathways was reported to play important roles in bone formation during DO . However, The studies of whether Fak‐Mapk pathway was activated or not during DO remain unclear.…”

“…Mechanical tension‐stress up‐regulated the entire Bmp pathway during DO . The spatial and temporal localization of Wnt pathway is increased, due to distraction strain, during DO . Meanwhile, some studies found the tension‐stress induced some genes and transcription factors up‐regulated or down‐regulated during DO .…”

Thy1 (CD90) expression is regulated by DNA methylation during adipogenesis

“…*P , 0.05, ***P , 0.001. through the activation of Wnt10a (30). Wnt10a is known to be up-regulated and essential for bone formation (53)(54)(55). However, Thy1 also has a critical role (56,57).…”

Dental and extra‐oral clinical features in 41 patients with WNT10A gene mutations: A multicentric genotype–phenotype study

“…Severe osteoporosis has also been diagnosed in WNT10A patient, including increased fracture risk and a pathological bone mineral density . Wnt pathway is in close molecular interaction with other crucial pathways, such as BMP and RANKL‐OPG via sclerostin, that are involved in skeletogenesis, bone metabolism and differentiation of osteochondroprogenitors toward an osteoblastic fate . Osteoblastogenesis is based on a specific Wnt level regulation, with reiterated up and down‐regulations of the Wnt pathway, highlighting the importance of the Wnt‐β‐catenin pathway in bone development .…”