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

Inubushi, T.; Kani, R.; Tanida, Y.; Usami, Y.; Iwayama, T.; Deyang, W.; Sasaki, J.-I.; Ye, J.; Kusano, S.; Shiraishi, Y.; Kurosaka, H.; Kopanja, D.; Takedachi, M.; Murakami, S.; Yamashiro, T.

doi:10.64898/2026.03.25.714159

bioRxiv · 10.64898/2026.03.25.714159

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

Inubushi, T.·Kani, R.·Tanida, Y.·Usami, Y.·Iwayama, T.·Deyang, W.·Sasaki, J.-I.·Ye, J.·Kusano, S.·Shiraishi, Y.·Kurosaka, H.·Kopanja, D.·Takedachi, M.·Murakami, S.·Yamashiro, T.

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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.

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Inubushi, T., Kani, R., Tanida, Y., Usami, Y., Iwayama, T., Deyang, W., Sasaki, J.-I., Ye, J., Kusano, S., Shiraishi, Y., Kurosaka, H., Kopanja, D., Takedachi, M., Murakami, S., Yamashiro, T.. 2026-03-27. A Wnt-responsive fibrocartilage progenitor system coordinates postnatal mandibular condylar cartilage growth. https://doi.org/10.64898/2026.03.25.714159

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