Abstract

Much of the vertebrate skeleton develops from cartilage templates that are progressively remodeled into bone. Lineage tracing studies in mouse suggest that chondrocytes within these templates persist and become osteoblasts, yet the underlying mechanisms of this process and whether chondrocytes can generate other derivatives remain unclear. We find that zebrafish cartilages undergo extensive remodeling and vascularization during juvenile stages to generate fat-filled bones. Growth plate chondrocytes marked by sox10 and col2a1a contribute to osteoblasts, marrow adipocytes, and mesenchymal cells within adult bones. At the edge of the hypertrophic zone, chondrocytes re-enter the cell cycle and express leptin receptor (lepr), suggesting conversion into progenitors. Further, mutation of matrix metalloproteinase 9 (mmp9) results in delayed growth plate remodeling and fewer marrow adipocytes. Our data support Mmp9-dependent growth plate remodeling and conversion of chondrocytes into osteoblasts and marrow adipocytes as conserved features of bony vertebrates.

Highlights

  • Vertebrate bones develop via two largely distinct processes

  • In order to characterize the progressive remodeling of an endochondral bone in zebrafish, we performed pentachrome staining on sections of the Ch bone from juvenile through adult stages (Figure 1)

  • The Ch is surrounded by a thin layer of cortical bone that has been shown to derive from osteoblasts located on the outside of the cartilage template (Paul et al, 2016)

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Summary

Introduction

Vertebrate bones develop via two largely distinct processes. Intramembranous (i.e. dermal) bone, which makes up a large portion of the skull, arises through the direct differentiation of mesenchymal precursors into osteoblasts and osteocytes. Chondrocytes at the edge of the developing hypertrophic zone largely disappear as the cartilage matrix is degraded, a process concurrent with the invasion of blood vessels, hematopoietic cells, and progenitors for osteoblasts and marrow adipocytes (Maes et al, 2010) This growth plate remodeling contributes to the establishment of trabecular bone, complementing the cortical bone largely derived from the periosteum, and the marrow cavity supports continued hematopoiesis. As the embryos started to form bones, the cartilage cells gave rise to bone cells, fat cells, and potentially adult stem cells within the marrow, which can become other types of cells This process required a protein called Mmp, which helps shape bone development in other organisms, including humans. Our studies reveal that growth plate chondrocytes generate osteocytes and adipocytes in zebrafish bones, potentially by transitioning through a proliferative intermediate

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