The art of building bone: emerging role of chondrocyte-to-osteoblast transdifferentiation in endochondral ossification

Abstract

There is a worldwide epidemic of skeletal diseases causing not only a public health issue but also accounting for a sizable portion of healthcare expenditures. The vertebrate skeleton is known to be formed by mesenchymal cells condensing into tissue elements (patterning phase) followed by their differentiation into cartilage (chondrocytes) or bone (osteoblasts) cells within the condensations. During the growth and remodeling phase, bone is formed directly via intramembranous ossification or through a cartilage to bone conversion via endochondral ossification routes. The canonical pathway of the endochondral bone formation process involves apoptosis of hypertrophic chondrocytes followed by vascular invasion that brings in osteoclast precursors to remove cartilage and osteoblast precursors to form bone. However, there is now an emerging role for chondrocyte-to-osteoblast transdifferentiation in the endochondral ossification process. Although the concept of “transdifferentiation” per se is not recent, new data using a variety of techniques to follow the fate of chondrocytes in different bones during embryonic and post-natal growth as well as during fracture repair in adults have identified three different models for chondrocyte-to-osteoblast transdifferentiation (direct transdifferentiation, dedifferentiation to redifferentiation, and chondrocyte to osteogenic precursor). This review focuses on the emerging models of chondrocyte-to-osteoblast transdifferentiation and their implications for the treatment of skeletal diseases as well as the possible signaling pathways that contribute to chondrocyte-to-osteoblast transdifferentiation processes.

Chondrocyte-Specific RUNX2 Overexpression Accelerates Post-traumatic Osteoarthritis Progression in Adult Mice

“…These cells eventually undergo apoptosis, or differentiate into cells of the osteoblast lineage, leaving behind a cartilaginous template upon which bone is formed and the primary ossification center established. (8)(9)(10)(11) Postnatally, secondary ossification centers form in the epiphyses to separate the transient growth plate cartilage from the permanent articular cartilage layer that lines the ends of the long bones. In contrast to the highly proliferative growth plate chondrocytes, articular chondrocytes at homeostasis are largely nonproliferative.…”

Regulation of terminal hypertrophic chondrocyte differentiation inPrmt5mutant mice modeling infantile idiopathic scoliosis

“…The formation of the vertebral bodies, like the long bones, ossify through a process of endochondral ossification where hypertrophic chondrocytes are replaced by and in some cases contribute to bone-forming osteoblast lineages (Aghajanian and Mohan, 2018). Our findings indicate that PRMT5 has an important role in the process of terminal differentiation of hypertrophic chondrocytes and endochondral bone formation, in part by positive regulation Mmp13 and RUNX2 expression and negative regulation of Ihh expression.…”

Mouse Wnt1-CRE-RosaTomato Dental Pulp Stem Cells Directly Contribute to the Calvarial Bone Regeneration Process

“…As observed in a classic endochondral process, hypertrophic chondrocyte‐like mDPSCs entered apoptosis at time points coincident with a decrease in their number in the morphometric analyses of the biphotonic images. Remarkably, Ds‐Red/Tomato positive cells were not observed near the newly formed bone, suggesting that none of them differentiate in osteoblasts, neither directly as in intramembranous bone formation nor by transdifferentiation . Host osteoblasts likely recruited by VEGF synthesized by the T‐mDPSC derived chondrocytes then deposit a type I collagen matrix efficiently mineralized.…”