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Abstract
One of the crucial steps in endochondral bone formation is the replacement of a cartilage matrix produced by chondrocytes with bone trabeculae made by osteoblasts. However, the precise sources of osteoblasts responsible for trabecular bone formation have not been fully defined. To investigate whether cells derived from hypertrophic chondrocytes contribute to the osteoblast pool in trabecular bones, we genetically labeled either hypertrophic chondrocytes by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using EGFP, LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. These in vivo experiments allowed us to follow the fate of cells labeled in Col10a1-Cre or Agc1-CreERT2 -expressing chondrocytes. After the labeling of chondrocytes, both during prenatal development and after birth, abundant labeled non-chondrocytic cells were present in the primary spongiosa. These cells were distributed throughout trabeculae surfaces and later were present in the endosteum, and embedded within the bone matrix. Co-expression studies using osteoblast markers indicated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts. Hence, our results show that both chondrocytes prior to initial ossification and growth plate chondrocytes before or after birth have the capacity to undergo transdifferentiation to become osteoblasts. The osteoblasts derived from Col10a1-expressing hypertrophic chondrocytes represent about sixty percent of all mature osteoblasts in endochondral bones of one month old mice. A similar process of chondrocyte to osteoblast transdifferentiation was involved during bone fracture healing in adult mice. Thus, in addition to cells in the periosteum chondrocytes represent a major source of osteoblasts contributing to endochondral bone formation in vivo.
Highlights
Long bones, ribs, vertebrae, and other parts of the vertebrate skeleton are formed through a precisely synchronized process known as endochondral ossification
During endochondral bone formation, which is responsible for the generation of most bones in mammals and many other species, osteoblasts deposit a bone-specific matrix on the surface of cartilage scaffolds made by chondrocytes and hypertrophic chondrocytes
We demonstrate that chondrocytes can transdifferentiate into osteoblasts and that these transdifferentiated osteoblasts represent a substantial fraction of the bone forming cells in mice, We provide evidence that chondrocytes can transdifferentiate into osteoblasts during bone fracture repair, a process similar to endochondral bone formation
Summary
Ribs, vertebrae, and other parts of the vertebrate skeleton are formed through a precisely synchronized process known as endochondral ossification. The highly complex endochondral bone tissue, which is generated through a cartilage intermediate, consists of multiple types of cells, including mesenchymal-derived chondrocytes, osteoblasts and osteocytes, as well as osteoclasts and bone marrow cells, which have a hematopoietic origin [1]. The conversion from the nonvascular cartilage template to fully mineralized endochondral bones proceeds in distinct and closely coupled steps [2]. The first step is initiated when chondrocytes in the center of the cartilage models undergo hypertrophic differentiation and cells in the perichondrium surrounding the hypertrophic zone differentiate into osteoblasts to form the interim bone cortex (bone collar). Following the onset of bone collar formation, hypertrophic chondrocytes and the mineralized cartilage matrix in the center of the cartilage template are replaced by a highly vascularized trabecular bone tissue as well as bone marrow. Bone trabeculae in the primary spongiosa are formed by deposition of osteoid by osteoblasts on the surface of calcified cartilage spicules
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