The fate of early perichondrial cells in developing bones

Abstract

In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. However, how early perichondrial cells distinctively contribute to developing bones remain unidentified. Here we show using in vivo cell-lineage analyses that Dlx5+ fetal perichondrial cells marked by Dlx5-creER do not generate cartilage but sustainably contribute to cortical bone and marrow stromal compartments in a manner complementary to fetal chondrocyte derivatives under the regulation of Hedgehog signaling. Postnatally, Dlx5+ fetal perichondrial cell derivatives preferentially populate the diaphyseal marrow stroma with a dormant adipocyte-biased state and are refractory to parathyroid hormone-induced bone anabolism. Therefore, early perichondrial cells of the fetal cartilage are destined to become an adipogenic subset of stromal cells in postnatal diaphyseal bone marrow, supporting the theory that the adult bone marrow stromal compartments are developmentally prescribed within the two distinct cells-of-origins of the fetal bone anlage.

Differential regulation of skeletal stem/progenitor cells in distinct skeletal compartments

“…This is where endochondral ossification begins, and skeletal compartments subsequently develop (Figure 2). GP formation starts off with early cartilage development through chondrocyte proliferation and differentiation of Fgfr3 + cells in the mesenchymal condensation (Ono and Kronenberg, 2016;Zieba et al, 2020;Matsushita et al, 2022). The proliferating chondrocytes become mature and later organize, through Notch signaling, at both sides of long bones as a tri-layer GP consisting of resting, proliferating, and hypertrophic chondrocyte zones (Ono and Kronenberg, 2016;Zieba et al, 2020).…”

“…Eventually, hypoxic condition in limb forming cells promotes vascular invasion to the perichondrium leading to osteoblast differentiation, and development of perichondrium to periosteum and articular soft tissues (Percival and Richtsmeier, 2013). The periosteum becomes a layer of connective tissue housing the proliferating progenitor cells with chondrogenic and osteogenic differentiation properties, while the osteoblasts differentiating mostly from Dlx5 + cells of the periosteum form a bony collar around the shaft of limb bones (Vanderbeck and Maillard, 2019;Sottoriva and Pajcini, 2021;Matsushita et al, 2022). Subsequently, the marrow cavity forms as long bones develop, and blood vessels invade the cartilage template from the osteogenic perichondrium, which are maintained through Notch signaling (Vanderbeck and Maillard, 2019;Sottoriva and Pajcini, 2021).…”

“…This is exemplified by the transition of fetal Osx + SSPCs to more long term postnatal Osx + BM SSPCs, and a shift from a more proliferative fetal Dlx5 + SSPCs to a more quiescent postnatal Dlx5 + BM-SSPCs. (Mizoguchi et al, 2014;Matsushita et al, 2022). With age, a subset of BM stoma cells further shifts towards adipocyte development (Taher et al, 2011;Bianco and Robey, 2015).…”

“…As mentioned earlier, BM forms during bone development with blood vessels invading through a layer of committed osteogenic cells. Osx + and Dlx5 + osteogenic precursor cells populate the forming fetal marrow with the development of the blood vessels (Maes et al, 2010;Liu et al, 2013;Matsushita et al, 2022). While both cells contribute to fetal periosteum and marrow stroma development, Osx + cells are transient as their number dramatically declined after 13 weeks, leaving Dlx5 + cells as the major BM-SSPCs with the role of regulating BM space formation (Mizoguchi et al, 2014;Matsushita et al, 2022).…”

“…Osx + and Dlx5 + osteogenic precursor cells populate the forming fetal marrow with the development of the blood vessels (Maes et al, 2010;Liu et al, 2013;Matsushita et al, 2022). While both cells contribute to fetal periosteum and marrow stroma development, Osx + cells are transient as their number dramatically declined after 13 weeks, leaving Dlx5 + cells as the major BM-SSPCs with the role of regulating BM space formation (Mizoguchi et al, 2014;Matsushita et al, 2022). Fgfr3 + cells contributing to the fetal cartilage template and fetal GP also form BM-SSPCs in embryonic trabecular bone formation, together with a subset of Osx + and Dlx5 + cells.…”