BMP-IHH-mediated interplay between mesenchymal stem cells and osteoclasts supports calvarial bone homeostasis and repair

Abstract

Calvarial bones are connected by fibrous sutures. These sutures provide a niche environment that includes mesenchymal stem cells (MSCs), osteoblasts, and osteoclasts, which help maintain calvarial bone homeostasis and repair. Abnormal function of osteogenic cells or diminished MSCs within the cranial suture can lead to skull defects, such as craniosynostosis. Despite the important function of each of these cell types within the cranial suture, we have limited knowledge about the role that crosstalk between them may play in regulating calvarial bone homeostasis and injury repair. Here we show that suture MSCs give rise to osteoprogenitors that show active bone morphogenetic protein (BMP) signalling and depend on BMP-mediated Indian hedgehog (IHH) signalling to balance osteogenesis and osteoclastogenesis activity. IHH signalling and receptor activator of nuclear factor kappa-Β ligand (RANKL) may function synergistically to promote the differentiation and resorption activity of osteoclasts. Loss of Bmpr1a in MSCs leads to downregulation of hedgehog (Hh) signalling and diminished cranial sutures. Significantly, activation of Hh signalling partially restores suture morphology in Bmpr1a mutant mice, suggesting the functional importance of BMP-mediated Hh signalling in regulating suture tissue homeostasis. Furthermore, there is an increased number of CD200+ cells in Bmpr1a mutant mice, which may also contribute to the inhibited osteoclast activity in the sutures of mutant mice. Finally, suture MSCs require BMP-mediated Hh signalling during the repair of calvarial bone defects after injury. Collectively, our studies reveal the molecular and cellular mechanisms governing cell–cell interactions within the cranial suture that regulate calvarial bone homeostasis and repair.

BMP Signaling in the Development and Regeneration of Cranium Bones and Maintenance of Calvarial Stem Cells

“…Gli1+ cells are more populous than the Prx1+ cells in the suture space. Gli1+ cells are detectable throughout the entire periosteum, dura, and suture mesenchyme at birth (Guo et al, 2018), but this pattern gradually becomes undetectable by 1 month postnatal, and Gli1+ cells are not detectable in fontanelles or osteocytes. Gli1+ cells eventually restricted to cranial sutures, including the fused posterior frontal suture, where they remain throughout adulthood (Zhao et al, 2015;Doro et al, 2017).…”

“…Gli1+ cells eventually restricted to cranial sutures, including the fused posterior frontal suture, where they remain throughout adulthood (Zhao et al, 2015;Doro et al, 2017). Gli1+ cells can contribute to osteogenic fronts, periosteum, and dura after tamoxifen treatment (Guo et al, 2018; Table 2). Axin2+ cells only label ∼15% of mesenchymal cells, and are highly restricted to the midline of the suture (Maruyama et al, 2016).…”

“…BMP2 is ectopically expressed in Gli3 mutant mesenchyme, which can lead to abnormal osteoblasts differentiation (Tanimoto et al, 2012). Osteoprogenitors from Gli1+ suture-derived stem cells was found to release Ihh, which is required to maintain the homeostasis of Gli1+ suture-derived stem cells, and this process is fine-tuned by BMPRIA (Guo et al, 2018). Further, the paracrine BMP2/BMP4, secreted by preosteoblasts, is principally required for the morphogenesis of dural cerebral veins (Tischfield et al, 2017), which then influence the state of the suturederived stem niche.…”

“…Interestedly, BMPRIA is reported to be a principal factor to regulate the homeostasis of Gli1+ suture-derived stem cells. Disruption of BMPRIA results in diminished cranial sutures and minimal healing ability (Guo et al, 2018). It suggested that suitable modulation of BMPs in suture-derived stem cells can facilitate bone regeneration following calvarial bone damage.…”

Glycosylation of DMP1 maintains cranial sutures in mice

“…9 Up to now, the known signalling involved in suture ossification includes the bone morphogenetic protein (BMP) signalling, the WNT signalling, the fibroblast growth factor (FGF) ligands and receptors (FGFR). 8,[10][11][12] Interestingly, besides above signalling molecules, new information indicates that a few extracellular matrix (ECM) molecules also play an important role in cranial sutures fusion. 13 The organic components of bone ECM were composed by collagens, non-collagenous extracellular matrix proteins, proteoglycans (PGs), and glycoprotein.…”