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Review
. 2021 Apr 21;22(9):4321.
doi: 10.3390/ijms22094321.

Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

Alessandra Guasto  1 , Valérie Cormier-Daire  1   2
Affiliations
Review

Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

Alessandra Guasto et al. Int J Mol Sci. .

Abstract

Bone development is a tightly regulated process. Several integrated signaling pathways including HH, PTHrP, WNT, NOTCH, TGF-β, BMP, FGF and the transcription factors SOX9, RUNX2 and OSX are essential for proper skeletal development. Misregulation of these signaling pathways can cause a large spectrum of congenital conditions categorized as skeletal dysplasia. Since the signaling pathways involved in skeletal dysplasia interact at multiple levels and have a different role depending on the time of action (early or late in chondrogenesis and osteoblastogenesis), it is still difficult to precisely explain the physiopathological mechanisms of skeletal disorders. However, in recent years, significant progress has been made in elucidating the mechanisms of these signaling pathways and genotype-phenotype correlations have helped to elucidate their role in skeletogenesis. Here, we review the principal signaling pathways involved in bone development and their associated skeletal dysplasia.

Keywords: bone development; signaling pathways; skeletal dysplasia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
HH and PTHrP signaling pathways in chondrocyte and osteoblast differentiation (A) HH ligands interact with PTCH 1 receptor causing the activation of the SMO protein and in consequence, the activation of GLI transcriptor factors. HH signaling positively regulates the first steps of chondrogenesis from mesenchymal stem cells (MSC) and chondrocyte proliferation. It induces the specification of osteoblast precursors and the maturation in mature osteoblasts. The activation of the GLI3 repressor (GLI3R) inhibits osteoblast precursor proliferation. (B) PTHrP or PTHLH bind to PTHR1 activating Gαs and Gαq proteins. Through Gαs, PTHrP activates adenylate cyclase and the production of cAMP, which in turn activates PKA proteins inducing chondrocyte proliferation and inhibiting their hypertrophic differentiation. However, through Gαq, PTHrP activates PLCβ and the production of DAG and IP3, leading to the activation of PKC and to an increase of intracellular Ca2+, respectively. PLCβ signaling inhibits chondrocyte proliferation and induces their hypertrophic differentiation and osteoblast differentiation.
Figure 2
Figure 2
WNT and NOTCH signaling pathways in chondrocyte and osteoblast differentiation. (A) WNT ligands bind to the FZD receptors with or without specific co-receptors like LRP5, LRP6 and ROR2. In the canonical pathway, WNT binding activates the translocation of β-catenin in the nucleus. This inhibits the first step of chondrogenesis but induces the chondrocyte hypertrophic differentiation and osteoblast differentiation and maturation. The non-canonical pathways, through the activation of DVL, JNK and PLC proteins, activate PKC and induce chondrocyte proliferation. WNT signaling can be negatively regulated by extracellular inhibitors, such as SOST, GREM1 and SFRP4, and by intracellular inhibitors, like AMER1. (B) In the NOTCH pathways, DLL or JAG ligands bind to NOTCH receptor and cause consequent proteolytic cleavages resulting in the release of NICD which translocate in the nucleus and interact with MAML1 and RBPJk proteins. NOTCH signaling inhibits chondrogenesis, and the first and the last stages of osteoblast differentiation, but promotes the differentiation of osteoprogenitors in osteoblast precursors.
Figure 3
Figure 3
TGFβ, BMP and FGF signaling pathways in chondrocyte and osteoblast differentiation. (A) TGF-β ligands bind to TGFBR type 1 and 2 causing the phosphorylation of the receptors and of SMAD 2 and 3 proteins which interact with SMAD4. This complex accumulates in the nucleus and induces chondrogenesis and osteoblastogenesis but inhibits the last step of chondrocyte and osteoblast maturation. SMAD activity can be blocked by intracellular inhibitors like SKI and LEMD3. (B) BMP ligands bind to BMPR type 1 and 2 causing the phosphorylation of the receptors and of SMAD 1, 5 and 8 proteins which interact with SMAD4. This complex accumulates in the nucleus and induces chondrocyte proliferation and all the steps of osteoblast differentiation. GDF ligands and the NOGGIN antagonist also bind BMPR. (C) FGF ligands bind FGFR causing receptor transphosphorylation, the phosphorylation of the adaptor protein FRS2α and the activation of STAT1, PLCγ and GRB2. GRB2 in turn activates PI3K and MAPK proteins. Through these pathways, FGF promotes chondrocyte proliferation and differentiation in the first step of the development and it promotes osteoblast proliferation and differentiation. In contrast, in the later stages of development, it inhibits chondrocyte proliferation and differentiation. MAPK signaling, downstream of FGFR, can be negatively regulated by the CNP-NPR pathway.
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