Regeneration of Jaw Joint Cartilage in Adult Zebrafish.

Joanna Smeeton,J Gage Crump,Peter Fabian,Troy Anderson,Natasha Natarajan,Kuo-Chang Tseng

doi:10.3389/fcell.2021.777787

Joanna Smeeton, J Gage Crump + Show 4 more

Open Access

https://doi.org/10.3389/fcell.2021.777787

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Abstract

The poor intrinsic repair capacity of mammalian joint cartilage likely contributes to the high incidence of arthritis worldwide. Adult zebrafish can regenerate many structures that show limited or no healing capacity in mammals, including the jawbone. To test whether zebrafish can also regenerate damaged joints, we developed a surgical injury model in which the zebrafish jaw joint is destabilized via transection of the major jaw joint ligament, the interopercular–mandibular (IOM). Unilateral transection of the IOM ligament in 1-year-old fish resulted in an initial reduction of jaw joint cartilage by 14 days, with full regeneration of joint cartilage by 28 days. Joint cartilage regeneration involves the re-entry of articular chondrocytes into the cell cycle and the upregulated expression of sox10, a marker of developing chondrocytes in the embryo that becomes restricted to a subset of joint chondrocytes in adults. Genetic ablation of these sox10-expressing chondrocytes shows that they are essential for joint cartilage regeneration. To uncover the potential source of new chondrocytes during joint regeneration, we performed single-cell RNA sequencing of the uninjured adult jaw joint and identified multiple skeletal, connective tissue, and fibroblast subtypes. In particular, we uncovered a joint-specific periosteal population expressing coch and grem1a, with the jaw joint chondrocytes marked by grem1a expression during regeneration. Our findings demonstrate the capacity of zebrafish to regenerate adult joint cartilage and identify candidate cell types that can be tested for their roles in regenerative response.

Highlights

Vertebrate synovial joints are complex structures composed of multiple integrated cell types, including osteoblasts, superficial and deeper chondrocytes, ligamentocytes, and connective tissue cells lining the synovium and adjacent periosteum of the underlying bone
Given the high prevalence of osteoarthritis in the adult population, new models of natural joint regeneration would be highly valuable in uncovering the capacity of tissue-resident progenitors for joint repair
We show that adult zebrafish display transient jaw joint degeneration in response to ligament transection, which is rapidly followed by the robust regeneration of missing joint cartilage and the re-establishment of normal joint architecture

Summary

Introduction

Vertebrate synovial joints are complex structures composed of multiple integrated cell types, including osteoblasts, superficial and deeper chondrocytes, ligamentocytes, and connective tissue cells lining the synovium and adjacent periosteum of the underlying bone. To understand the complex cellular changes underlying arthritis progression and the failure of resident cells to counteract joint degeneration, recent studies have focused on cataloging jointresident cells in normal and diseased states (Ji et al, 2019; Bian et al, 2020; Sebastian et al, 2021). As these have been performed in largely non-regenerative mammals (primarily mouse and human), it has been difficult to define putative endogenous progenitor populations with latent capacity for joint repair. One exception is the temporomandibular jaw joint (TMJ) of mouse, an unusual joint with a fibrocartilaginous disc that has been shown to possess fibrocartilage stem cells that can form self-renewing colonies in vitro and repair the damaged TMJ in vivo (Embree et al, 2016; Bi et al, 2020)

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