A Wnt-responsive fibrocartilage progenitor system coordinates postnatal mandibular condylar cartilage growth

Abstract

Postnatal growth of the mandibular condyle requires coordinated expansion of fibrocartilage and production of chondrocytes, yet the cellular populations that organize this process remain incompletely defined. Here we identify a Wnt-responsive fibrocartilage progenitor population that contributes to postnatal mandibular condylar cartilage growth. Using a direct Wnt activity reporter (R26-WntVis), inducible genetic lineage tracing (Axin2CreERT2), and single-cell transcriptomics, we define a Wnt-enriched progenitor-like cluster localized predominantly within the fibrocartilage zone. Lineage tracing demonstrates that Axin2-lineage cells expand laterally within fibrocartilage and generate vertically aligned chondrocytes in the chondrocartilage compartment, indicating bidirectional growth contribution in vivo. Conditional ablation of {beta}-catenin in Axin2-lineage cells results in depletion of the fibrocartilage compartment and premature activation of chondrogenic differentiation programs, whereas constitutive {beta}-catenin activation disrupts compartmental organization without enhancing proliferation. Mechanistically, we identify Foxm1 as a Wnt-associated proliferative mediator enriched in fibrocartilage, and genetic reduction of Foxm1 cooperates with {beta}-catenin deficiency to impair condylar growth. In parallel, {beta}-catenin loss derepresses TGF-{beta}-Smad signaling and enhances chondrogenic differentiation, indicating that canonical Wnt activity coordinates proliferative maintenance while restraining lineage commitment within the same cellular compartment. Together, these findings identify a Wnt-responsive fibrocartilage progenitor system that regulates postnatal mandibular condylar cartilage growth by coupling Foxm1-associated proliferative maintenance with suppression of TGF-{beta}-dependent chondrogenic differentiation during temporomandibular joint development. Graphical abstractWnt-responsive fibrocartilage progenitors coordinate postnatal mandibular condylar cartilage growth through Foxm1-dependent proliferative maintenance and suppression of TGF-{beta}-driven chondrogenic differentiation.