IntroductionMesenchymal stem cells (MSCs) are stem/progenitor cells for bone, cartilage, and hematopoietic-supporting marrow stroma (including bone-lining cells, fibroblasts, reticulocytes, adipocytes, and pericytes). However, the fundamental study of these intriguing cells is currently limited by uncertainties regarding their ontology, in vivo identity, and developmental potential. This is complicated by the lack of molecular markers and standard isolation procedures and by difficulties in studying MSCs in mouse models. [1][2][3] Recently, 2 different studies provided evidence that undifferentiated mesenchymal cells are present in murine embryonic perichondrium during endochondral bone formation. [4][5][6][7] These cells were shown to adopt a pericyte identity while migrating from the perichondrium to colonize both the bone collar (cortical bone) and the primary spongiosa (trabecular bone). Moreover, these cells were shown to participate in fracture repair in postnatal bones. These observations are significant because they are the first to unambiguously demonstrate that perichondrium-derived cells participate in both cortical bone and trabecular bone formation and give rise to osteostromal progenitors that have a marrow perivascular niche, which was previously proposed for human MSCs. 8,9 Moreover, these studies reconcile contradictory reports demonstrating the presence of MSCs in cortical bone, trabecular bone, periosteum, and the marrow/periosteal perivascular space. [10][11][12][13][14][15][16] Endochondral bone formation, homeostasis, and repair are highly orchestrated processes involving cellular proliferation, migration, differentiation, and apoptosis, as well as cross-talk between the growth plate, perichondrium/periosteum, cortical and trabecular bone, marrow stroma, and invading vasculature and hematopoietic cells. [17][18][19] In addition to mechanical, nervous, and endocrine stimulation, these events are largely mediated by soluble factors such as PDGF, TGF-, BMPs, Wnts, parathyroid hormonerelated protein (PTHrP), Indian hedgehog (Ihh), and FGFs, and their associated receptors. The FGF family comprises 22 ligands displaying high levels of homology, redundancy, and promiscuity. There are 4 known FGF receptors (FGFRs) expressed as multiple splice variants, and 3 of them are involved in bone formation: FGFR1, FGFR2, and FGFR3. FGFs/FGFRs are expressed in a tissue-specific manner, are developmentally regulated, and are crucial for bone formation, maintenance, and repair. 20 However, the large number of ligands and receptor isoforms, as well as their redundancy and promiscuity, makes the study of their roles in endochondral bone formation a particular challenge. The mitogenic effect of FGF-2 on MSCs in vitro has long been observed, and studies have also shown that FGF-2 promotes undifferentiated proliferation of MSCs in vitro. [21][22][23][24][25] However, given the importance of FGFs/FGFRs in bone, it is surprising that this system has not yet been described in more detail in MSCs.In the present study, ...