On the evolutionary relationship between chondrocytes and osteoblasts

Abstract

Vertebrates are the only animals that produce bone, but the molecular genetic basis for this evolutionary novelty remains obscure. Here, we synthesize information from traditional evolutionary and modern molecular genetic studies in order to generate a working hypothesis on the evolution of the gene regulatory network (GRN) underlying bone formation. Since transcription factors are often core components of GRNs (i.e., kernels), we focus our analyses on Sox9 and Runx2. Our argument centers on three skeletal tissues that comprise the majority of the vertebrate skeleton: immature cartilage, mature cartilage, and bone. Immature cartilage is produced during early stages of cartilage differentiation and can persist into adulthood, whereas mature cartilage undergoes additional stages of differentiation, including hypertrophy and mineralization. Functionally, histologically, and embryologically, these three skeletal tissues are very similar, yet unique, suggesting that one might have evolved from another. Traditional studies of the fossil record, comparative anatomy and embryology demonstrate clearly that immature cartilage evolved before mature cartilage or bone. Modern molecular approaches show that the GRNs regulating differentiation of these three skeletal cell fates are similar, yet unique, just like the functional and histological features of the tissues themselves. Intriguingly, the Sox9 GRN driving cartilage formation appears to be dominant to the Runx2 GRN of bone. Emphasizing an embryological and evolutionary transcriptomic view, we hypothesize that the Runx2 GRN underlying bone formation was co-opted from mature cartilage. We discuss how modern molecular genetic experiments, such as comparative transcriptomics, can test this hypothesis directly, meanwhile permitting levels of constraint and adaptation to be evaluated quantitatively. Therefore, comparative transcriptomics may revolutionize understanding of not only the clade-specific evolution of skeletal cells, but also the generation of evolutionary novelties, providing a modern paradigm for the evolutionary process.

Simulation Enabled Search for Explanatory Mechanisms of the Fracture Healing Process

“…2) Have sustained directional influences, spanning many TUs, guiding or constraining the direction and type of TU transitions. The latter may map to the combined net effects of multiple factors such as relative abundance and activity of immune cells [43] signaling influencing osteogenic and chondrogenic transcription networks [44], O2 gradients [45,46], and mechanical influences [47]. Callus Analog has achieved its current objectives without needing to bring any of those influences into focus, consistent with our strong parsimony guideline.…”

A Single-cell Transcriptomic Atlas of the Developing Chicken Limb

“…However, in mammals only RSPO2 , and not RSPO3 , seems to be implicated in AER function [42–44]. Similarly, species-specific modifications in the gene regulatory networks driving skeletal cell type maturation have been reported [45, 46]. Together with recent scRNA-seq studies in other vertebrate model organisms [30, 47, 48], our dataset now opens new avenues for a comprehensive assessment of molecular similarities and divergences in patterning-relevant cell populations of the developing limb, across all major tetrapod clades.…”

“…Module Red shows enrichment for many canonical markers of chondrocyte maturation (Fig. 6e) [45, 51]. On the other hand, genes in module Turquoise do not, for the most part, evoke a classical chondrogenic transcriptional profile (Fig.…”

Signaling pathways regulating cartilage growth plate formation and activity

“…The fact that both osteoblasts and chondrocytes are derived from the same Sox9 -expressing osteochondro-progenitors hints at their potential common gene regulatory networks. Indeed, the transcription factors involved in chondrocyte and osteoblast differentiation serve complementary functions in the development of cartilage and bone [157]. In addition to their own specific markers such as Col10a1 , hypertrophic chondrocytes also express many osteoblast markers, including Alp , SPARC , BGLAP , Opn , and Bsp , as well as Osx and Runx2 , albeit at relatively lower levels compared with their expressions in osteoblasts [158, 159].…”