Dynamic regulation of fibroblast heterogeneity in regeneration repair and bone diseases

Bone healing is a complex, systems-level process traditionally viewed through the lens of mesenchymal stromal cells (MSCs) and osteoblast-lineage cells. However, recent evidence suggests that fibroblasts represent a substantial fraction of lesion cellularity, far exceeding MSCs. These cells are no longer considered passive "fillers" but are recognized as active niche organizers that implement the information architecture of repair, including matrix topology and cytokine gradients.

This review aims to synthesize recent findings on fibroblast heterogeneity in the context of skeletal repair. It addresses the inconsistent terminology surrounding "fibroblasts" and "MSCs" and emphasizes a three-dimensional coordinate system-cell type, anatomical niche, and repair stage-to understand their functional diversity. The review specifically focuses on periosteal and marrow fibroblasts as archetypal reservoirs for controllable niche organization.

The review explores three major regulatory pillars: signaling pathways, metabolic reprogramming, and intercellular communication. Key signaling networks such as Wnt/β-catenin, BMP, and Hedgehog are integrated with mechanotransduction (YAP/TAZ) to steer fibroblast trajectories toward either regeneration or fibrosis. Metabolism acts as a "gate," where a switch from glycolysis to oxidative phosphorylation (OXPHOS) is required for successful osteogenic commitment. Finally, the review details how fibroblasts coordinate repair through an intercellular network involving extracellular vesicles, gap junctions, and paracrine gradients, synchronizing responses across different anatomical niches.