# Spatial Transcriptomics of TMJ Reveals a Remodeling Fibroblast‐Immune Microenvironment Driving Arthritis Pain

## TL;DR

This study uses spatial transcriptomics to map cell types in the TMJ and reveals how fibroblast-immune interactions drive arthritis pain.

## Contribution

The study introduces a detailed spatial cell atlas of the TMJ and identifies a fibroblast-immune crosstalk mechanism via the Igf1-Il33 axis in arthritis pain.

## Key findings

- Spatial transcriptomics identified new TMJ cell types and their anatomical locations.
- Arthritis induces changes in cell numbers and states, with fibroblast-immune microenvironment remodeling.
- Macrophage Igf1 and fibroblast Il33 signaling drive inflammation and pain in TMJ arthritis.

## Abstract

Temporomandibular joint (TMJ) arthritis remodels the cartilage, subchondral bone, and synovial tissue with diverse cell changes. The functional importance of the anatomical organization of TMJ cell types and cellular microenvironment in painful arthritis remains largely unknown. Here, we applied seqFISH (sequential Fluorescence In Situ Hybridization) spatial transcriptomics to examine the adult mouse TMJ. We uncovered new cell types and comprehensively mapped anatomical locations of diverse cell types with distinct neighborhoods, revealed arthritis‐induced cell number and cell status changes, and discovered microenvironment remodeling of fibroblast‐immune cells, which are confirmed in patient synovial tissues. Functional and mechanistic studies showed that macrophage‐specific knockout of mouse Igf1 promotes its immune activation and upregulates Il33 in adjacent synovial fibroblasts, resulting in inflammatory fibroblast expansion. In turn, fibroblast‐specific deletion of Il33 alleviates inflammatory macrophages and inflammation, leading to pain mitigation. Thus, spatial transcriptomics maps diverse cell types in TMJ and reveals a remodeling of synovial fibroblast‐immune microenvironment via the Igf1‐Il33 axis, which drives arthritis pain with therapeutic potentials.

Spatial transcriptomics reveals a remodeled fibroblast‐immune microenvironment in the temporomandibular joint (TMJ) during arthritis. By combining seqFISH with genetic mouse models, this study uncovers TMJ spatial cell atalas, macrophage‐fibroblast crosstalk, and cytokine signaling pathways driving TMJ inflammation and pain. These findings provide new cellular insights into TMJ arthritis and open avenues for targeted therapies in orofacial pain disorders.