Medication-Related Osteonecrosis of the Jaw: New Insights into Molecular Mechanisms and Cellular Therapeutic Approaches

Figure 2

Molecular regulation of MSCs during bone formation. (a) Ihh pathway: Indian hedgehog (Ihh) stimulates, directly or indirectly (through the parathyroid hormone-related peptide (PTHrp) synthesis), chondrocytes proliferation and their differentiation into hypertrophic or larger cells. Ihh binds to its receptor Patched (Ptch), which inhibits Smoothened (Smo). The resulting activation of Smo leads to an increase of intracellular concentration of Gli proteins (Gli activator (GliA) and Gli repressor (GliR)) subsequent of the inhibition of their degradation regulated by glycogen synthase kinase (GSK3β), protein kinase A (PKA), and casein kinase (CSK). After translocation into the nucleus, Gli activator could bind to its promoter and stimulate various genes’ expression, especially Runx2 [11, 12]. (b) PTH and PTHrp pathway: parathyroid hormone (PTH) and parathyroid hormone-related (PTHrp) bind to PTH-receptor1 (PTHr1), which is a G protein-coupled receptor that activates adenylate cyclase. This leads to cAMP production, PKA and PKC stimulation, and Runx2 expression. The exact mechanism leading to Runx2 is still unknown. (c) BMP pathway: bone morphogenetic proteins (BMPs) binds to a tetrameric receptor encompassing type I (BMPR1) and type II (BMPR2) receptors that are serine-threonine kinases. The receptor activation induces signal transduction through Smads or mitogen-activated protein kinase (MAPK). Smads are cytoplasmic molecules that are classified into 3 subsets: (1) receptor-regulated Smads (Smads 1, 2, 3, 5, and 8); (2) common-partner Smads (Smad 4); (3) inhibitory Smads (Smads 6, 7). Smads 1, 5, and 8 are activated by phosphorylation induced by BMPs interacting with their receptors. Receptor-regulated phosphorylated Smads are then able to form a dimeric complex with Smad 4 allowing its nuclear translocation. When phosphorylated, Smads 6 and 7 both inhibit Smads 1, 5, and 8 phosphorylation and Smad 4 linking [13]. In the nucleus, the dimeric Smad complex will induce the target genes expression such as Runx2, distal-less homeobox 5 (Dlx5), and osterix (Osx) which are osteoblastic genes [14, 15]. (d) Wnt-β catenin canonical pathway: Wnt molecules are involved in multiple cell functions, including osteogenesis. Wnt-1, Wnt-3a, Wnt-4, Wnt-5, Wnt-10b, and Wnt-13, are essential in bone formation [16]. Wnt binds to its receptor Frizzled (Fzd) and coreceptor, low-density lipoprotein receptor-related protein (Lrp). In absence of binding, dishevelled (Dsh) remains inactivated in the cytoplasm and β catenin can form a complex with GSK3β, adenomatous polyposis coli (APC), and axin that leads to their degradation by ubiquitination. When Wnt binds to its receptor, phosphorylated Dsh induces axin and GSK3β inhibition and thus leads to β-catenin accumulation. β-Catenin is then able to translocate into the nucleus where it drives the target genes expression. (e) MAPK pathway: mitogen-activated protein kinases (MAPKs) are able to phosphorylate and inhibit GSK3β and Smads 1, 5, and 8 activities. They are also able to induce Runx2 and Dlx5 expression. MAPK can be triggered by epithelial growth factor (EGF), fibroblast growth factor (FGF), and BMPs.

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