Understanding the Cellular and Molecular Mechanisms That Control Early Cell Fate Decisions During Appendicular Skeletogenesis

Abstract

The formation of the vertebrate skeleton is orchestrated in time and space by a number of gene regulatory networks that specify and position all skeletal tissues. During embryonic development, bones have two distinct origins: bone tissue differentiates directly from mesenchymal progenitors, whereas most long bones arise from cartilaginous templates through a process known as endochondral ossification. Before endochondral bone development takes place, chondrocytes form a cartilage analgen that will be sequentially segmented to form joints; thus, in the cartilage template, either the cartilage maturation programme or the joint formation programme is activated. Once the cartilage differentiation programme starts, the growth plate begins to form. In contrast, when the joint formation programme is activated, a capsule begins to form that contains special articular cartilage and synovium to generate a functional joint. In this review, we will discuss the mechanisms controlling the earliest molecular events that regulate cell fate during skeletogenesis in long bones. We will explore the initial processes that lead to the recruitment of mesenchymal stem/progenitor cells, the commitment of chondrocyte lineages, and the formation of skeletal elements during morphogenesis. Thereafter, we will review the process of joint specification and joint morphogenesis. We will discuss the links between transcription factor activity, cell–cell interactions, cell–extracellular matrix interactions, growth factor signalling, and other molecular interactions that control mesenchymal stem/progenitor cell fate during embryonic skeletogenesis.

Lessons from joint development for cartilage repair in the clinic

“…[138][139][140][141] The MSCs at the periphery of the limb bud are maintained in an undifferentiated state by molecular signals (specifically FGF8 and WNT3A) which are released from the apical ectodermal ridge (AER) and surrounding ectoderm respectively. 58,[142][143][144][145][146] However, in the center of the limb bud, away from the control of these signals, MSCs aggregate into the mesenchymal condensations to form the skeletal anlage. From the early stages of limb development, the anlage appears to be composed of distinct cell populations which give rise to specific cell lineages and sub-lineages, and ultimately to different skeletal structures (Figure 3).…”

“…The development of the appendicular skeletal elements requires the proliferation and migration of mesenchymal cells from the LPM to form the limb bud 138‐141 . The MSCs at the periphery of the limb bud are maintained in an undifferentiated state by molecular signals (specifically FGF8 and WNT3A) which are released from the apical ectodermal ridge (AER) and surrounding ectoderm respectively 58,142‐146 . However, in the center of the limb bud, away from the control of these signals, MSCs aggregate into the mesenchymal condensations to form the skeletal anlage.…”

Transcription Factors of the Alx Family: Evolutionarily Conserved Regulators of Deuterostome Skeletogenesis

“…In vertebrates, as noted above, the embryonic lineages of cells in the limbs and limb girdles that express alx1-related genes have not been mapped precisely, although many of these cells are presumably derived from the somatic layer of the lateral plate mesoderm, a major source of limb skeletal tissue. There is evidence that chondrocytes and osteoblasts of the limb are derived from a common, mesenchymal precursor cell and that the specialization of these two cell types depends upon regulatory functions of sox9 (a member of a small number of paralogous, soxE-family genes in vertebrates) and other sox genes in the chondrogenic lineage, and runx2 and osterix in the osteoblast lineage (Akiyama et al, 2005;Cervantes-Diaz et al, 2017;Lefebvre, 2019;Marín-Llera et al, 2019). Because alx-related genes have not been linked directly to the regulatory network that underlies limb skeletogenesis, and because Sox and Runx proteins are not currently known to be associated with skeleton formation in echinoderms, there is presently no obvious similarity between the GRN circuitry that controls skeletal development in the vertebrate limb and the echinoderm skeleton.…”

Menaquinone-7 Supplementation Improves Osteogenesis in Pluripotent Stem Cell Derived Mesenchymal Stem Cells

“…Further, differentiating cells from pluripotency toward mesenchymal and osteogenic lineage enables application of a novel tool for interrogation of developmental pathways and phenotypes in bone formation (Yousefi et al, 2016 ). This can potentially answer age-old questions with regards to mechanisms of endochondral transdifferentiation, and the role of macrophages in bone formation (Setty, 2014 ; Cho, 2015 ; Dogan, 2018 ; Haraguchi et al, 2019 ; Marín-Llera et al, 2019 ). Present methods of determination of osteogenic processes include detection of osteoblastic markers such as RUNX2, Col1A1, and Osterix along with ALP activity and calcium deposition (Svandova et al, 2020 ; Yong et al, 2020 ).…”