Skeletogenesis: Genetics

Abstract

The vertebrate skeleton is formed by two mechanisms – endochondral and intramembranous ossification. During intramembranous ossification, mesenchymal cells directly differentiate into osteoblasts. Endochondral ossification is a two‐step process during which bones are preformed as cartilage templates, which are subsequently replaced by bone. During this process, the inner cells of the cartilage condensation differentiate into chondrocytes, which proliferate and differentiate into hypertrophic chondrocytes producing a mineralised matrix. The outer cells differentiate into the perichondrium surrounding the cartilage template and later into osteoblasts, which produce a bone collar surrounding the hypertrophic region. Blood vessels from the bone collar invade the hypertrophic region in close association with bone‐resorbing osteoclasts and bone‐forming osteoblasts. The orchestrated formation, differentiation and degradation of cartilage and bone are regulated by a multitude of growth factors and transcriptional regulators, which will be discussed in this article. Key Concepts: During intramembranous ossification, mesenchymal progenitor cells differentiate directly into bone‐forming osteoblasts. Endochondral ossification includes the formation of cartilage templates, which are subsequently replaced by bone and bone marrow. Cells in the cartilage condensation represent bipotential osteochondroprogenitor cells that differentiate depending on their level of Sox9 into chondrocytes. Ihh serves as a key regulator of endochondral ossification regulating chondrocyte proliferation, hypertrophic differentiation and ossification. Ihh and Pthrp interact in a negative feedback mechanism to control the domain of columnar, high‐proliferating chondrocytes. Pthrp negatively regulates cell cycle exit. Runx2 and Mef2c activate chondrocyte differentiation. Runx2 and Osterix are required to induce osteoblast differentiation. The balance between Rankl and osteoprotegerin determines the differentiation of osteoclasts. Chondrocyte differentiation is regulated by secreted growth factors, which activate distinct steps of the differentiation programme.

Probing Multicellular Tissue Fusion of Cocultured Spheroids—A 3D‐Bioassembly Model

“…[ 72 ] Our study indicates that culturing different cell populations in distinct hierarchical zones, without initial close contact, can modulate the extent of cell proliferation over time, whereas direct and close exposure to paracrine signaling between mixed cell sources accelerates proliferation early on, simply due to increased exposure to multicellular factors. Chondrocytes transitioning to a fibroblast‐like phenotype typically display high cellular proliferation rate and low GAG production [ 73–76 ] while hMSCs are known to undergo a series of sequential biological processes to regenerate musculoskeletal tissue: condensation, overt differentiation, proliferation, maturation, hypertrophy, and finally replacement of chondrocytes by osteoblasts and calcified tissue. [ 77–79 ] While it is not possible to distinguish if the modest increase in DNA during coculture is due to hAC‐ or hMSC‐specific proliferation/apoptosis, or a combinations thereof, it indicates that the majority of cells remain in a healthy, low‐proliferative, chondrogenic differentiation phase throughout the culture period across all the investigated culture arrangements.…”