Oral and maxillofacial surgery is often challenging due to defective bone healing owing to the microbial environment of the oral cavity, the additional involvement of teeth and esthetic concerns. Insufficient bone volume as a consequence of aging and some oral and maxillofacial surgical procedures, such as tumor resection of the jaw, may further impact facial esthetics and cause the failure of certain procedures, such as oral and maxillofacial implantation. Bone morphogenetic protein (BMP) 9 (BMP9) is one of the most effective BMPs to induce the osteogenic differentiation of different stem cells. A large cross-talk network that includes the BMP9, Wnt/β, Hedgehog, EGF, TGF-β and Notch signaling pathways finely regulates osteogenesis induced by BMP9. Epigenetic control during BMP9-induced osteogenesis is mainly dependent on histone deacetylases (HDACs), microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which adds another layer of complexity. As a result, all these factors work together to orchestrate the molecular and cellular events underlying BMP9-related tissue engineering. In this review, we summarize our current understanding of the SMAD-dependent and SMAD-independent BMP9 pathways, with a particular focus on cross-talk and cross-regulation between BMP9 and other major signaling pathways in BMP9-induced osteogenesis. Furthermore, recently discovered epigenetic regulation of BMP9 pathways and the molecular and cellular basis of the application of BMP9 in tissue engineering in current oral and maxillofacial surgery and other orthopedic-related clinical settings are also discussed.

Introduction

Oral and maxillofacial surgery often aims for both functional and esthetic outcomes, both of which are mostly dependent on the underlying bones. Defective bone healing is a significant challenge during surgery owing to the microbial environment of the oral cavity, the additional involvement of teeth and esthetic concerns [1,2]. Surgical procedures, such as apical surgery on teeth close to the maxillary sinus and implantation in oral and maxillofacial regions, need sufficient bone volume to achieve favorable outcomes [3,4]. Unfortunately, in addition to the natural inadequacy and resorption of bones with increasing age, traditional tooth extraction [5], tumor resection [6] and critical-sized maxillofacial fracture treatment [7] often exacerbate bone volume deficiency, which may lead to substantial jaw defects. Therefore, there is an urgent need to develop a predictable and safe procedure to restore or generate sufficient bone volume during oral and maxillofacial surgeries.

Bone morphogenetic protein (BMP) 9 (BMP9), also known as growth differentiation factor 2 (GDF2), was first found in the fetal mouse liver [8] and is thought to participate in multiple physiological and pathological functions, such as osteogenesis, chondrogenesis, angiogenesis and tumorigenesis [9–12]. Previous studies have demonstrated that among the at least 14 BMPs found in the BMP family, BMP9 has the most potent bone-forming capability [13]. Sufficient evidence indicates that BMP9 is responsible for osteogenesis via a complicated network of signaling pathways [14–17], which involves not only the SMAD-dependent BMP9 signaling pathway but also SMAD-independent pathways and cross-regulation with other representative signaling pathways during osteogenesis. In addition, it has gradually been recognized that almost all physiological and pathological processes related to bones are tightly regulated by epigenetic control mechanisms [18–20]. Reports on the essential role of epigenetic factors in osteogenesis related to BMP9 signaling have also emerged rapidly.

Previous reviews have mainly emphasized the importance of the SMAD-dependent BMP9 pathway and the mechanism at the protein level [21,22], but an overall view of crossregulatory elements and the current knowledge of BMP9 and epigenetics has yet to be reported. This review summarizes the current understanding of the molecular mechanisms underlying both the SMAD-dependent and SMAD-independent BMP9 pathways, with a particular focus on cross-talk and cross-regulation between different signaling pathways in BMP9-induced osteogenesis. Furthermore, the epigenetic regulation of BMP9 pathways and possible insight into the clinical therapeutic application of BMP9-induced osteogenesis in tissue engineering and regenerative medicine are also discussed, which could serve as a molecular and cellular basis to benefit orthopedic-related surgical procedures, including but not limited to oral and maxillofacial surgeries.

A brief introduction to BMP9 signaling pathways

SMAD-dependent BMP9 signaling pathway

The BMP9–SMAD pathway, also known as the canonical or SMAD-dependent BMP9 signaling pathway, is the best-studied molecular mechanism of BMP9-stimulated osteogenesis (Figure 1). Similar to detailed reports in former reviews [21,22], both the BMP9 homodimer and the BMP9/BMP10 heterodimer can interact with type II BMP receptors and then phosphorylate type I BMP receptors to further initiate the phosphorylation of SMAD1/5/8 [23]. Phosphorylated SMAD1/5/8 then binds SMAD4 to form the SMAD1/5/8-SMAD4 complex, which ultimately translocates into the nucleus, where it regulates the transcription of osteogenic-related genes, such as RUNX2, Dlx5 and Osx [23,24].

SMAD-dependent and SMAD-independent BMP9 signaling pathways during osteogenesis.

Figure 1.
SMAD-dependent and SMAD-independent BMP9 signaling pathways during osteogenesis.

The BMP9 homodimer or BMP9/BMP10 heterodimer can interact with type II receptors and then phosphorylate type I receptors to initiate the phosphorylation of SMAD1/5/8. Phosphorylated SMAD1/5/8 then binds SMAD4 to translocate into the nucleus, where it regulates the transcription of osteogenic-related genes. SMAD6 and SMAD7 inhibit BMP9 signaling via (1) competitively binding the phosphorylation site of BMP receptors and (2) meditating ubiquitin–proteasome-regulated degradation by recruiting Smurf1. Ubc9 may negatively regulate BMP9 signaling via SUMO modification of SMAD4. BMP9 shows resistance to Noggin; however, evidence has shown that CV2 can inhibit BMP9 signaling. In the SMAD-independent pathway, phosphorylated TAK1 can recruit TAB1 to initiate the downstream MKK–p38 MAPK or MKK–ERK1/2 signal.

Figure 1.
SMAD-dependent and SMAD-independent BMP9 signaling pathways during osteogenesis.

The BMP9 homodimer or BMP9/BMP10 heterodimer can interact with type II receptors and then phosphorylate type I receptors to initiate the phosphorylation of SMAD1/5/8. Phosphorylated SMAD1/5/8 then binds SMAD4 to translocate into the nucleus, where it regulates the transcription of osteogenic-related genes. SMAD6 and SMAD7 inhibit BMP9 signaling via (1) competitively binding the phosphorylation site of BMP receptors and (2) meditating ubiquitin–proteasome-regulated degradation by recruiting Smurf1. Ubc9 may negatively regulate BMP9 signaling via SUMO modification of SMAD4. BMP9 shows resistance to Noggin; however, evidence has shown that CV2 can inhibit BMP9 signaling. In the SMAD-independent pathway, phosphorylated TAK1 can recruit TAB1 to initiate the downstream MKK–p38 MAPK or MKK–ERK1/2 signal.

Several studies have proposed multiple regulatory mechanisms targeting different steps in the SMAD-dependent BMP9 signaling pathway. The overexpression of both SMAD6 and SMAD7, which are frequently referred to as I-SMADs, could inhibit BMP-induced osteoblast differentiation and osteogenesis, and these effects could be reversed by the down-regulation of these I-SMADs [25–27]. At least two distinct pathways have been indicated to be involved in this inhibitory process: (1) competitive binding to the phosphorylation site of BMP receptors and (2) mediating ubiquitin/proteasome-regulated degradation by recruiting Smurf1, an E3 ubiquitin ligase. Conversely, Arkadia, another E3 ubiquitin ligase, could induce the ubiquitination and degradation of both SMAD6 and SMAD7 and increase BMP-related osteogenesis. The only major component common to both the SMAD-dependent TGF-β and BMP pathways is SMAD4, and ubiquitin-conjugating enzyme 9 (Ubc9) has been reported to negatively regulate osteoblastic differentiation events induced by BMP, possibly via the modification of SMAD4 with small ubiquitin-related modifier (SUMO).

Interestingly, it is worth noting that regulation of the BMP9 signaling pathway may have another layer of complexity: BMP9-induced osteogenesis was not affected by Noggin, a traditional and well-known BMP ligand trap [28,29]. This finding can be interpreted as the result of either a lack of the Noggin-binding domain in BMP9 or, at least in part, BMP9 signaling through the SMAD-independent pathway, as well as the presence of a large cross-talk network between BMP9 pathways and other representative osteogenic signaling pathways.

SMAD-independent BMP9 signaling pathway

Current knowledge suggests that some elements of the mitogen-activated protein kinase (MAPK) signaling pathway are involved in the SMAD-independent BMP9 signaling pathway in a TAK1/TAB1–MKK–p38 MAPK/ERK-dependent manner (Figure 1). The inhibition of p38 MAPK through either a selective inhibitor or siRNA could block BMP9-induced osteogenic differentiation [23], which is consistent with the decrease in p38 MAPK and morphological defects observed in BMP receptor conditional knockout (cKO) mice [30]. TAK1 is involved in the fine tuning of BMP signaling during osteogenesis [31–33]. The loss of TAK1 caused the activation of both p38 MAPK and the BMP/SMAD signaling pathway [32,33]. Clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to haploinsufficiency of runt-related transcription factor 2 (RUNX2) in humans, were found in osteoblasts in which TAK1 had specifically been deleted [34]. Further study revealed that RUNX2 was phosphorylated via the TAK1–MKK3/6–p38 MAPK pathway, associated with the co-activator CREB-binding protein (CBP) during osteogenesis [34]. The evidence above illustrates an alternative SMAD-independent BMP9 signaling pathway; however, the role of ERK during BMP9-induced osteogenesis remains unclear. Early studies found that the activation of markers downstream of BMP9-induced osteogenesis was increased by the inhibition of ERK1/2 through either a selective inhibitor or siRNA [23,35]. In contrast with the inhibitory effect on osteogenesis presented above [23,35], a recent study showed decreased activation of osteoblast master regulators in a Mek1 and Mek2 deletion model both in vitro and in vivo [36]. Notably, Mek1 and Mek2 are kinases upstream of ERK/MAPK, which indicates that ERK may promote osteogenesis [36]. A possible explanation for the dual functions of ERK is that the BMP9-ERK axis has multiple downstream targets and that ERK can bind different targets to activate different functions in a dose-dependent manner. Furthermore, after concerns were raised about the redundant data in one study [35] after its publication, the article was retracted by the related editors [37]. As a result, further studies should draw more attention to clarifying the detailed mechanism of ERK in the SMAD-independent BMP9 signaling pathway.

Cross-talk between the BMP9 pathway and other representative osteogenic signaling pathways

It is widely recognized that the cellular signaling symphony during osteogenesis includes several dynamic, major signaling pathways, such as the BMP, Wnt, Hedgehog, EGF, TGF-β and Notch signaling pathways [16,17,38–40]. Different signaling pathways may interact and engage in cross-talk via either a positive or negative feedback loop, which is important for maintaining bone homeostasis (Figure 2).

Cross-talk between BMP9 and other representative signaling pathways during osteogenesis.

Figure 2.
Cross-talk between BMP9 and other representative signaling pathways during osteogenesis.

BMP9 plays dual roles in Wnt/β catenin signaling. (1) BMP9 promotes Wnt/β catenin signaling via PI3K-Akt or FAK to inhibit GSK3β. SMAD4 and Tcf/Lef complexes compete for β-catenin to maintain osteoblast proliferation and matrix synthesis. (2) Wnt inhibitors Dkk1 and Sost can be up-regulated by BMP9 signaling. Hedgehog signaling accelerates the translocation and accumulation of p-SMAD1/5/8 in the nucleus, and transcriptional factors such as Gli1 may act as co-activators of the SMAD complex. EGF can induce BMP9 expression, whereas EGFR expression is directly up-regulated by BMP9 through the SMAD1/5/8 signaling pathway. TGF-β and BMP9 can competitively bind the same receptor. Notch signaling promotes osteogenesis via the Hey1–RUNX2 axis, but NICD can inhibit JunB to further inhibit downstream osteogenic signaling.

Figure 2.
Cross-talk between BMP9 and other representative signaling pathways during osteogenesis.

BMP9 plays dual roles in Wnt/β catenin signaling. (1) BMP9 promotes Wnt/β catenin signaling via PI3K-Akt or FAK to inhibit GSK3β. SMAD4 and Tcf/Lef complexes compete for β-catenin to maintain osteoblast proliferation and matrix synthesis. (2) Wnt inhibitors Dkk1 and Sost can be up-regulated by BMP9 signaling. Hedgehog signaling accelerates the translocation and accumulation of p-SMAD1/5/8 in the nucleus, and transcriptional factors such as Gli1 may act as co-activators of the SMAD complex. EGF can induce BMP9 expression, whereas EGFR expression is directly up-regulated by BMP9 through the SMAD1/5/8 signaling pathway. TGF-β and BMP9 can competitively bind the same receptor. Notch signaling promotes osteogenesis via the Hey1–RUNX2 axis, but NICD can inhibit JunB to further inhibit downstream osteogenic signaling.

Cross-talk between BMP9 and the Wnt/β catenin signaling pathway

The Wnt/β catenin signaling pathway has indispensable effects on osteogenesis [39,41]. During the activation of Wnt/β catenin signaling, Wnt ligands first bind Frizzled and LRP receptors, which further recruit and activate the destruction complex and Dvl. GSK-3β is then inhibited by activated Dvl, resulting in the reduced degradation, accumulation and translocation of β-catenin, which promotes the expression of several downstream target genes [39,41,42].

Chromatin immunoprecipitation (ChIP) analysis showed that BMP-9 can recruit both β-catenin and RUNX2 to the osteocalcin promoter, which was correlated with diminished BMP9-induced osteocalcin reporter activity and the expression of late markers of osteogenesis in β-catenin-knockdown mesenchymal stem cells (MSCs) and mouse embryonic fibroblasts (MEFs) [43]. To maintain the balance between osteoblast proliferation and matrix synthesis, β-catenin is bound by SMAD4 or Tcf/Lef complexes competitively [44]. The conditional deletion of SMAD4 in osterix+ cells in mice resulted in increased osteoblast proliferation but decreased matrix synthesis [44], which was also confirmed in cranial neural crest stem cells [45]. Focal adhesion kinase (FAK) plays a critical role in many biological processes. A recent study revealed that FAK may inhibit GSK-3β to attenuate osteoblast proliferation and promote adipogenic differentiation in bone marrow [46]. Additional studies indicated that BMP9 could obviously increase FAK phosphorylation by affecting Wnt and intact SMAD-dependent BMP9 signaling in both adipose-derived stem cells (ADSCs) and synovial mesenchymal stem cells (SMSCs) [47,48]. In addition to FAK, BMP9 can directly activate GSK3β-β-catenin signaling independent of Wnt protein secretion via the class I PI3K-Akt axis, which has also been implicated as a potential cross-talk pathway between BMP9 and Wnt/β catenin signaling [49].

Evidence has shown that the expression of the Wnt inhibitors Dkk1 and Sost is down-regulated in the bones of Bmpr1a cKO mice [50] and up-regulated in BMP9-induced osteoblasts and MSCs [28,51]. Furthermore, the expression of Sost was not regulated by p38 MAPK because no response to selective protein inhibitors was observed in BMP-pretreated osteoblasts, which was different from the effect on Dkk1 expression under the same conditions [50,51].

Cross-talk between BMP9 and the hedgehog pathway

After relieving the inhibitory function of Ptch by Hedgehog ligands, Smo could positively activate and translocate downstream transcriptional factors mostly belonging to the Gli protein family. Hedgehog signaling has been proven to participate in a variety of developmental processes in the oral and maxillofacial regions[52–55], and BMP may be involved [54]. The reduction or augmentation of markers of osteogenic differentiation was found after the inhibition or enhancement of Hedgehog signaling using cyclopamine or purmorphamine in BMP9-induced MSCs [17]. At the same time, BMP9-induced transcriptional activities of SMAD1/5/8 were increased or decreased in the same manner [17], which may be the underlying mechanism by which Hedgehog signaling accelerates the translocation and accumulation of p-SMAD1/5/8 in the nucleus, or transcription factors such as Gli1 may act as co-activators of the SMAD complex.

Cross-talk between BMP9 and the EGF pathway

Evidence has shown that EGF can induce BMP9 expression in MSCs, whereas EGFR expression is directly up-regulated by BMP9 through the SMAD1/5/8 signaling pathway [16]. The EGF signaling pathway plays a significant role in epiphyseal cartilage development and endochondral ossification [56,57]. In addition, EGF signaling shows the ability to activate several key signaling pathways, such as the Ras–Raf–ERK MAPK pathway [58]. The EGF signal itself seems to have a negligible effect on osteogenic differentiation in MSCs [16]. This finding correlates with previous findings that EGF may promote the proliferation and expansion of osteoprogenitors at the expense of further lineage-specific differentiation [59,60]. As a result, a logical theory based on the above facts is that EGF signaling effectively proliferates and expands osteoprogenitors, after which BMP9 promotes advanced lineage commitment and terminal differentiation.

Cross-talk between BMP9 and the TGF-β pathway

TGF-β signaling is a double-edged sword in regard to factors related to osteogenic differentiation. TGF-β1 signaling alone is unable to induce osteogenesis in MSCs but can promote the accumulation of osteoprogenitors through proliferation and chemotaxis [61,62]. Several active type II TGF-β receptors, such as BMPRII and ActRII, are required for BMP9-induced osteogenesis in MSCs [63], which indicates that TGF-β and BMP9 may competitively bind the same receptor. On the one hand, evidence shows that TGF-β1 signaling blocks osteoblast apoptosis [64,65], but on the other hand, TGF-β1 signaling also inhibits osteoblast differentiation and mineralization [66,67]. One study suggested that TGF-β1 plays a biphasic role in the BMP9-induced osteogenesis of MSCs in a dose-dependent manner. In detail, a low concentration of TGF-β1 led to the expression of osteogenic markers, whereas a higher concentration of TGF-β1 decreased the expression of osteopontin and osteocalcin [68]. Further studies should be conducted to clarify the direct mechanism of cross-talk between BMP9 and the TGF-β pathway.

Cross-talk between BMP9 and the Notch signaling pathway

Notch signaling is often activated when direct contact occurs between two neighboring cells [40,69]. The Notch signaling pathway transduces signals through enzymatic cleavage and hydrolysis rather than through phosphorylation. The Notch intracellular domain (NICD) is released after multiple cleavage events and can target downstream genes related to skeletal development and homeostasis with transcription factors such as CSL [40,69].

Several studies have suggested that Notch signaling activation augments BMP9-induced osteogenic differentiation and osteogenesis [9,15,70,71]. The Notch inhibitor dnNotch1 and genetic disruption of Notch signaling in PS1/PS2 double-knockout mice could significantly suppress BMP9-induced osteogenic differentiation both in vitro and in ectopic bone [70]. In addition to osteogenesis, the stimulation of MSCs with both BMP9 and NICD1 yielded extensive vascularization after implantation of the cells in a biocompatible scaffold. The induction of key angiogenic factors by BMP9 was further enhanced by NICD1 in MSCs in ectopic bone, and this effect was reversed by dnNotch1 [9]. BMP9-induced osteogenic differentiation was significantly suppressed by Ad-dnALK2, and this inhibition was rescued by Ad-DLL1 in MSCs. This finding suggests that the DLL1/Notch axis up-regulates ALK2, a BMP receptor, to further enhance BMP9-induced osteogenesis [15]. The Notch downstream target Hey1 can be up-regulated by BMP9, indicating that BMP9 may act as an upstream mediator of Notch signaling [72]. In addition, impaired osteogenic differentiation caused by Hey1 knockdown could be rescued through RUNX2 overexpression [72], suggesting a pathway for the interplay between BMP9-Notch signaling. Interestingly, Notch signaling alone seemed insufficient to activate de novo osteogenesis and ectopic bone formation in MSCs, which further confirmed that the Notch axis is mediated by BMP9 signaling [9,72].

Adding a layer of controversy and complexity, one study reported that Notch signaling may inhibit the expression of JunB and eventually inhibit osteogenesis induced by BMP9 in MSCs [73]. Previous evidence showed that RUNX2 expression induced by BMP could be down-regulated by dominant-negative c-fos (A-fos), which inhibited jun family-dependent activation, while a potent JunB activator, TPA, could significantly up-regulate JunB and RUNX2 [73–75]. This indicated that JunB may participate in BMP signaling, and the down-regulated expression of JunB after NICD treatment suggests a potential mechanism of this inhibitory effect.

The total effect of Notch signaling on BMP9-induced osteogenesis appears to be determined by the net balance of the above opposing mechanisms in the cell under physiological milieus. Since most of these findings describe indirect mechanisms, another explanation for the inconsistencies between studies is the involvement of epigenetic control, especially the diverse effects of long noncoding RNAs (lncRNAs) in BMP9-related biological processes [71,76].

The roles of epigenetic regulation in BMP9-induced osteogenesis

Epigenetics is the study of relatively stable changes in gene expression caused by DNA modification and associated information-rich factors, rather than the DNA sequence itself; these changes can be influenced by the environment and may be maintained during cell division [77]. The development and maintenance of bone and related structures require not only genetic control but also rapid and dynamic epigenetic modifications [19,78]. Lineage commitment and the subsequent osteogenic differentiation of MSCs involve three major mechanisms of epigenetic modification: DNA methylation, chromatin structure modulation and noncoding RNAs (ncRNAs) [20,38,79].

DNA methylation and chromatin structure modulation

DNA methylation describes the covalent addition of a methyl group to cytosines in DNA (Figure 3A), especially in CpG islands [20]. The structure of chromatin itself and the spatial organization of DNA and its cofactors, such as histones, also play important roles in the functional readout of the genome. The N-terminal tails of histones are well-known sites that can be posttranslationally modified by methylation, acetylation, phosphorylation, and ubiquitylation (Figure 3A), which in turn are related to processes such as transcription, DNA repair and damage, and DNA replication [80,81]. BMP9 can induce most histone deacetylases (HDACs) in MSCs [82]. The inhibition of HDACs using the HDAC inhibitor trichostatin A potentiated the osteogenic markers alkaline phosphatase, osteocalcin and osteopontin, and augmented bone formation ability was further confirmed in fetal limb explants [82].

Epigenetic and BMP9 signaling pathways.

Figure 3.
Epigenetic and BMP9 signaling pathways.

(A) Schematic of DNA methylation and histone acetylation. (B) Schematic of four essential regulatory roles of lncRNA regulatory mechanisms. Signal: lncRNAs can be transcribed as signals, some of which can even regulate downstream targets. Decoy: lncRNAs can either competitively bind and inhibit target proteins or regulate miRNAs through ceRNA mechanisms. Guide: lncRNAs can bind target proteins to guide them to their target DNAs. Scaffold: lncRNAs bind multiple transcription factors or multiple downstream effectors from different signaling pathways to further integrate the output of total effects. (C) Noncoding RNAs in BMP9-induced osteogenesis.

Figure 3.
Epigenetic and BMP9 signaling pathways.

(A) Schematic of DNA methylation and histone acetylation. (B) Schematic of four essential regulatory roles of lncRNA regulatory mechanisms. Signal: lncRNAs can be transcribed as signals, some of which can even regulate downstream targets. Decoy: lncRNAs can either competitively bind and inhibit target proteins or regulate miRNAs through ceRNA mechanisms. Guide: lncRNAs can bind target proteins to guide them to their target DNAs. Scaffold: lncRNAs bind multiple transcription factors or multiple downstream effectors from different signaling pathways to further integrate the output of total effects. (C) Noncoding RNAs in BMP9-induced osteogenesis.

ncRNAs in BMP9-induced osteogenesis

Only a small portion of the human genome (1%–2%) is committed to protein synthesis, although almost 90% of genomic DNA can be transcribed into RNA [83]. This large proportion of noncoding segments, said to be a ‘huge disappointment’, was later investigated at the end of the Human Genome Project and confirmed based on potential epigenetic regulatory values. These ncRNAs play a significant role in gene expression by participating in at least transcription, posttranscriptional modification and translation [84,85]. Consequently, some suggestions have been made for an expansion of the current knowledge of epigenetic modification to include the mechanisms of ncRNAs [20,86]. Based on length, ncRNAs can be divided into two groups: lncRNAs (>200 nucleotides) and small ncRNAs (<200 nucleotides). Table 1 summarizes recently discovered ncRNAs involved in BMP9-related topics [71,76,87–91].

Table 1
Recent findings regarding ncRNAs in BMP9-related topics
ncRNADownstream target(s)Model(s)Disease backgroundUseful conclusionReference
microRNA-155 RUNX2 and BMPR2 In vitro, HEK-293, C2C12 and MEF cell lines
In vivo, subcutaneous ectopic osteogenesis in nude mice 
Bone diseases, osteogenic differentiation MicroRNA-155 inhibits BMP9-induced osteogenesis by targeting RUNX2 and BMPR2. [90
microRNA-21 SMAD7 In vitro, HEK-293, HCT116, C2C12 and MEFs cell lines Bone diseases, osteogenic differentiation MicroRNA-21 could promote osteogenic diffrentiation by suppressing SMAD7 in BMP9-stimulated murine multilineage cells. [87
lncRNA H19 Several miRNAs which may target Notch receptors and ligands In vitro, iMEFs, iMADs;
in vivo, subcutaneous injections of iMEFs infected with different adenoviruses into the flanks of athymic nude mice 
Bone diseases, osteogenic differentiation LncRNA H19 was significantly up-regulated after early BMP9 stimulation of MSCs, followed by a sharp decrease and return to baseline.
Either overexpressing or silencing lncRNA H19 led to increased expression of miRNAs targeting both Notch ligands and receptors. 
[71
lncRNA Rmst Several miRNAs which may target Notch receptors and ligands In vitro, iMADs
in vivo, subcutaneous injections of iMADs infected with different adenoviruses into the flanks of athymic nude mice 
Bone diseases, osteogenic differentiation LncRNA Rmst was significantly induced by BMP9 via SMAD signaling pathway in MSCs.
LncRNA Rmst may act as a decoy (ceRNA) of several miRNAs targeting Notch receptors and ligands to promote osteogenesis. 
[76
lncRNA UCA1 — In vitro, human bladder cancer BIU-87 and T24 cells
In vivo, subcutaneously inoculating tumor cells into male nude mice (5–6 weeks) and rasing for another 3 weeks 
Bladder cancer, cancer cell proliferation and migration BMP9 can increase the expression of lncRNA UCA1 by activating AKT. [88
lncRNA ITGB2-AS1 ITGB2 In vitro, human breast cell line MDA-MB-231 and MCF-7 Breast cancer, cancer cell proliferation and migration BMP9 could significantly decrease the expression of lncRNA ITGB2-AS1 in the MDA-MB-231 and MCF-7 cell lines.
LncRNA ITGB2-AS1 could promote breast cancer cells migration and invasion by up-regulating ITGB2. 
[91
lncRNA HULC BMP9 In vitro, ADSCs primary cell Urethral reconstruction, epithelial and smooth-muscle-like differentiation LncRNA HULC may become a promoter during the epithelial and smooth muscle-like differentiation of ADSCs through the BMP9/Wnt/β-catenin/Notch network. [89
ncRNADownstream target(s)Model(s)Disease backgroundUseful conclusionReference
microRNA-155 RUNX2 and BMPR2 In vitro, HEK-293, C2C12 and MEF cell lines
In vivo, subcutaneous ectopic osteogenesis in nude mice 
Bone diseases, osteogenic differentiation MicroRNA-155 inhibits BMP9-induced osteogenesis by targeting RUNX2 and BMPR2. [90
microRNA-21 SMAD7 In vitro, HEK-293, HCT116, C2C12 and MEFs cell lines Bone diseases, osteogenic differentiation MicroRNA-21 could promote osteogenic diffrentiation by suppressing SMAD7 in BMP9-stimulated murine multilineage cells. [87
lncRNA H19 Several miRNAs which may target Notch receptors and ligands In vitro, iMEFs, iMADs;
in vivo, subcutaneous injections of iMEFs infected with different adenoviruses into the flanks of athymic nude mice 
Bone diseases, osteogenic differentiation LncRNA H19 was significantly up-regulated after early BMP9 stimulation of MSCs, followed by a sharp decrease and return to baseline.
Either overexpressing or silencing lncRNA H19 led to increased expression of miRNAs targeting both Notch ligands and receptors. 
[71
lncRNA Rmst Several miRNAs which may target Notch receptors and ligands In vitro, iMADs
in vivo, subcutaneous injections of iMADs infected with different adenoviruses into the flanks of athymic nude mice 
Bone diseases, osteogenic differentiation LncRNA Rmst was significantly induced by BMP9 via SMAD signaling pathway in MSCs.
LncRNA Rmst may act as a decoy (ceRNA) of several miRNAs targeting Notch receptors and ligands to promote osteogenesis. 
[76
lncRNA UCA1 — In vitro, human bladder cancer BIU-87 and T24 cells
In vivo, subcutaneously inoculating tumor cells into male nude mice (5–6 weeks) and rasing for another 3 weeks 
Bladder cancer, cancer cell proliferation and migration BMP9 can increase the expression of lncRNA UCA1 by activating AKT. [88
lncRNA ITGB2-AS1 ITGB2 In vitro, human breast cell line MDA-MB-231 and MCF-7 Breast cancer, cancer cell proliferation and migration BMP9 could significantly decrease the expression of lncRNA ITGB2-AS1 in the MDA-MB-231 and MCF-7 cell lines.
LncRNA ITGB2-AS1 could promote breast cancer cells migration and invasion by up-regulating ITGB2. 
[91
lncRNA HULC BMP9 In vitro, ADSCs primary cell Urethral reconstruction, epithelial and smooth-muscle-like differentiation LncRNA HULC may become a promoter during the epithelial and smooth muscle-like differentiation of ADSCs through the BMP9/Wnt/β-catenin/Notch network. [89

Among small ncRNAs, microRNAs (miRNAs, 18–25 nucleotides) are the most widely studied subset. The inhibition of protein synthesis by binding the 3′-untranslated region (UTR) of corresponding mRNA(s) is the major mechanism of miRNA-related epigenetic regulation [20]. Recent studies have revealed the importance of miRNAs in BMP9-induced osteogenesis (Figure 3C). The overexpression of miRNA-21 potentiated the osteogenesis process by promoting BMP9-induced osteogenic differentiation by targeting SMAD7 mRNA [87]. Furthermore, miRNA-155 was found to inhibit BMP9-induced osteogenic differentiation by binding the 3′-UTR of RUNX2 and BMPRII mRNA [90].

In recent studies, lncRNAs have rapidly gained considerable attention that is mainly focused on their regulatory effects. As the underlying mechanisms of lncRNAs have been unraveled, many clues about their diverse biological functions have been discovered, and some of this emerging evidence contradicts conventional concepts about genes and disease [84,92,93]. It is important to stress the four essential roles of lncRNAs in regulatory mechanisms: signal, decoy, guide, and scaffold [92] (more details are discussed in Figure 3B and the corresponding figure legends).

BMP9 treatment regulates the expression of multiple lncRNAs, and in turn, these lncRNAs feedback regulate BMP9 signaling [71,76,88,89,91]. During BMP9-induced osteogenesis (Figure 3C), the lncRNA Rmst acts as a decoy for Notch-targeting miRNAs, which can further enhance osteogenic differentiation by fine-tuning BMP9-Notch signaling cross-talk [76]. Interestingly, a study found that at the early stage of BMP9 stimulation, the expression of lncRNA H19 was increased, which was correlated with up-regulated early osteogenic markers in BMP9-stimulated stem cells. Either the overexpression or silencing of lncRNA H19 led to the up-regulation of miRNAs targeting both Notch receptors and ligands, which could significantly impair BMP9-induced osteogenic differentiation both in vitro and in vivo [71].

The therapeutic potential of BMP9-induced osteogenesis

Unique advantages of BMP9-induced osteogenesis

In contrast with other BMP family members, BMP9 shows the most effective performance in inducing osteogenesis [94]. A comparative experiment including recombinant human BMP2, BMP7 and BMP9 treatments provided a reasonable explanation for the superior osteogenic ability of BMP9; among the three treatments, rhBMP9 treatment resulted in a significantly higher phosphorylation rate of SMAD1/5/8 and a significantly higher level of alkaline phosphatase activity than the other two treatments [28]. BMP9 signaling activity can be further increased via the rhBMP9-dependent negative regulation of Smurfs, thus decreasing the decomposition of SMADs [28]. Moreover, BMP9 can induce other BMP family members, such as RGMb, a coreceptor for rhBMP2 [63], which indicates that BMP9 can co-operate with other BMPs to further enhance and mediate its own signaling. As mentioned in the preceding part of this review, BMP9 signaling can interact with other major signaling pathways during osteogenesis. The cross-talk network provides another perspective to recognize the unique mechanism of osteogenic differentiation induced by BMP9 compared with other BMPs. A comprehensive transcriptomic analysis of the stimulation of the 14 types of BMPs in MSCs confirmed the above idea that with at least equal activation rates of other major pathways during osteogenesis in MSCs, BMP9 can significantly activate Wnt receptors, such as Frizzled receptors, and induce less expression of Wnt inhibitors, such as Sost, than other osteogenic BMPs [13].

As a widely accepted concept, bone healing is a complex procedure that may involve the coordination of several cells, signaling pathways and microenvironments [95]. Blood vessels adjacent to the bone formation region serve as transportation channels and bone structure templates [96,97]. In contrast with BMP2, the BMP9-dependent angiogenetic potential of MSCs has been reported in a growing body of studies. The BMP9-induced expression of RUNX2 directly regulates angiogenic factors, such as VEGF, vWF and ANGPT1, in human amniotic MSCs [98]. The SMAD-dependent BMP9 pathway can induce hypoxia-inducible factor 1α (HIF1α), which can synergistically up-regulate BMP9-induced angiogenic and osteogenic activities [99]. Epidermal growth factor-like domain 7 (EGFL7) is a master regulator of angiogenesis [100]. The deletion of EGFL7 by CRISPR/Cas9 in BMP9-stimulated human embryonic stem cells further confirmed the critical role of BMP9-induced endothelial sprouting and the cross-talk among BMP9, Notch, ERK and VEGF signaling pathways [101]. The reciprocity between BMP9 and Notch signaling during osteogenesis and angiogenesis has also been confirmed in a previously mentioned study [9]. However, it is worth noting that BMP9-induced angiogenesis has another layer of complexity: several studies demonstrated antiangiogenic functions of BMP9 in multiple types of endothelial cells. In addition to the significant differences in cell type among studies, another possible explanation is the large variation in the BMP9 dosage among studies. Compared with using a relatively high dose of BMP9 (10 ng/ml) [102,103], 1 ng/ml BMP9 can successfully induce angiogenesis in MSCs [101].

Clinical application of BMP9 in orthopedic or oral and maxillofacial surgery

Currently, at least 300 million people are affected by bone diseases, such as osteoporosis, worldwide [104,105]. Approximately half of the osteoporosis patients will encounter one or more bone fractures, which may significantly affect the quality of life and life expectancy [104,105]. Incidents, such as road traffic accidents and sports injuries, are another common cause of complicated fractures [106].

The possible poor prognosis in the repair of complicated bone defects, which are often seen in oral and maxillofacial surgeries [106], is largely due to insufficient bone volume regeneration. Several surgical techniques, such as oral and maxillofacial implantation, are also dependent upon sufficient bone volume at the surgical site. Autogenous bone grafts, the clinical gold standard in orthopedic-related surgery, is usually associated with concerns regarding additional complications and morbidity at both the donor and recipient sites, prolonged hospital stays and the need for further rehabilitation [107,108]. Emerging methods in tissue engineering have provided improved insight into these long-standing problems.

Theoretically, the three key factors required for successful tissue engineering are cell signaling factors (such as BMP9), seed cells and scaffolds (Figure 4A) [109]. The viral delivery of growth factors is not acceptable in clinical practice owing to concerns about safety issues; as an alternative, recombinant human proteins can act more safely to deliver growth factors. The US Food and Drug Administration has approved the use of rhBMP2 in several neurosurgical and orthopedic surgical procedures [28]. However, together, the high cost, possible lack of response to rhBMP2 treatment, and side effects, including hematoma, soft tissue swelling or even the need for advanced airway support, reflect the need for new candidate cell signaling factors, especially those that can be utilized at lower doses, such as rhBMP9 [28,110,111]. As mentioned above, MSCs are usually applied as seed cells in bone tissue engineering. Clinically, stem cells come from different sources, such as bone marrow, adipose tissue and dental tissue. During oral and maxillofacial surgery, they can be applied either in situ with autogenous scaffolds, such as particulate bone marrow and cancellous bone, or ex vivo, in which MSCs from the patient are isolated, expanded, proliferated and predifferentiated ex vivo on three-dimensional scaffolds. Various scaffolds can work as frameworks and carriers to deliver and support cell signaling factors and stem/regenerative cells. Thermoresponsive polydiolcitrate-gelatin (PPCNg) scaffolds showed excellent osteoinductive and osteoconductive capabilities with good biocompatibility during BMP9-induced osteogenesis both in vitro and in ectopic bone [112,113]. Moreover, the combination of a nanoparticulate mineralized glycosaminoglycan scaffold and BMP9 stimulated the osteogenic and chondrogenic differentiation of MSCs in vitro [114].

Possible applications of BMP9 in orthopedic-related tissue engineering.

Figure 4.
Possible applications of BMP9 in orthopedic-related tissue engineering.

(A) Schematic of BMP9 applications based on three key factors of tissue engineering. (B) The composite allogenic approach in current clinical scenarios, especially in oral and maxillofacial surgical procedures.

Figure 4.
Possible applications of BMP9 in orthopedic-related tissue engineering.

(A) Schematic of BMP9 applications based on three key factors of tissue engineering. (B) The composite allogenic approach in current clinical scenarios, especially in oral and maxillofacial surgical procedures.

The use of BMPs has been generally accepted in several procedures in the orthopedic and neurosurgical fields, such as techniques to address bone defects/insufficient bone volume or osteoarthritis and techniques to perform interbody spinal fusion (Figure 4A) [7,115,116]; additionally, preclinical in vitro and in vivo studies on the viral delivery of BMP9 in these diseases have shown excellent performance with no significant side effects [117,118]. Increased bone induction was detected following treatment with rhBMP9 at a lower dose than that of rhBMP2 and rhBMP7 [28,110], indicating drastic reductions in intake dose, dose-related side effects and total cost. A recent study reported that combination treatment with BMP2 and BMP9-stimulated joint regeneration after digit amputation in mice [119]. Collagen sponges with rhBMP9 induced more bone than collagen sponges with rhBMP2 in calvarial critical-sized defects in mice [7]. Together, these BMP9-related preclinical studies reveal promising clinical implications for successful tissue engineering and relevant surgical procedures.

Most related oral and maxillofacial cases are attributed to bone defects/insufficient bone volume, which indicates a bright future for the application of BMP9 in oral and maxillofacial tissue engineering.

Notably, slightly different from the bone tissue engineering theory in papers, current clinically achievable bone regeneration techniques usually use multiple types of seed cells (multiple types of cells at donor sites), scaffolds (autologous, allogeneic or xenogeneic) and cell signaling factors [120]. Moreover, a single element used in clinical bone regeneration techniques may correlate with multiple roles described in bone tissue engineering theory, e.g. the allogenic bone used in oral and maxillofacial bone regeneration techniques in daily practice can provide seed cells, act as a scaffold and may even contain some growth factors [121]. A composite allogenic approach that combines BMPs, bone marrow aspirate concentrates (BMACs) or platelet-rich derivates, and allogenic bone shows predictable and successful surgical outcomes during tissue engineering procedures [107,122]. Therefore, the general strategy derived from the above findings has been widely accepted by different teams, especially teams of oral and maxillofacial surgeons, who need more delicate and predictable control over procedures in esthetic areas, such as the mandible during mandibular reconstruction (Figure 4B). Moreover, when a patient has insufficient bone volume, such as an atrophic alveolar ridge or atrophic bone structures close to the maxillary sinus, implants in these areas are usually considered unacceptable or require more complicated and risky procedures [123,124]. With improved bone regeneration techniques, surgeons are obligated to perform conservative alveolar ridge preservation/augmentation to try to preserve/reconstruct the natural shape of the alveolar ridge before directly proposing more risky procedures, such as the placement of zygomatic implants. Before maxillary sinus floor augmentation techniques were widely carried out clinically, the failure rate of posterior maxillary implants was significantly higher than that of implants at other anatomical sites [125] due to maxillary sinus pneumatization, which can further reduce the available bone volume in patients with an atrophic alveolar ridge (Figure 4B). A composite approach including rhBMP9 used in alveolar ridge preservation/augmentation after tooth extraction showed higher bone-inducing potential than treatment with rhBMP2 [126], highlighting the greater possibility of clinical success in alveolar ridge augmentation and probably maxillary sinus floor augmentation. The concept of guided bone regeneration (GBR) incorporates barrier membranes to isolate fast-growing epithelial and connective tissue from an alveolar wound to ensure that relatively slow-growing bone tissues occupy the space [127]. Combined with a barrier membrane and bone grafts, GBR is frequently used in alveolar ridge augmentation. GBR procedures can also benefit from including rhBMP9. rhBMP9 loaded in either collagen barrier membranes or bone grafts significantly enhanced bone formation, and collagen membranes loaded with rhBMP9 led to better wound healing [128]. A randomized clinical trial showed that implant abutments treated with TiO2 on the surface promoted the release of BMP9, which improved the early sealing of the implant-abutment collar and the rate of long-term success [129], but the underlying cellular events still need to be investigated.

Conclusion

Current evidence shows that BMP9 has excellent potential as a growth factor in oral and maxillofacial tissue engineering and other orthopedic-related procedures. As in the philosophy conveyed in ancient Chinese Taoism, the greatest truths are the simplest. In this case, this lesson reminds us that understanding the essential signaling processes in BMP9-induced osteogenesis is important. Cross-talk between several major signaling pathways, such as the Wnt/β, Hedgehog, EGF, TGF-β and Notch pathways, illustrates a very large crossregulatory network that can deepen our understanding of the biological characteristics of BMP9 signaling. In addition to the canonical BMP9/SMAD pathway, the SMAD-independent pathway, which contains elements of MAPK signaling, shows potential in osteoblast differentiation and osteogenesis. Because of contradictory reports on the role of ERK in the SMAD-independent BMP9 pathway, further experimental research is required to elucidate the more detailed mechanism involved. The complexity of epigenetic control during BMP9-induced osteogenesis mainly depends on HDACs, miRNAs and lncRNAs, based on current evidence. Further elucidating the effects and mechanisms of lncRNAs will help us to deeply understand the mechanism of BMP9 at the molecular level, providing an accurate intervention target in osteogenesis and differentiation. BMP9 tissue engineering products have become an exciting and clinically acceptable research topic, and a composite allogenic approach may become a regular paradigm in most BMP9-related tissue engineering strategies in oral and maxillofacial surgery. Notably, during embryogenesis, tooth development occurs almost simultaneously with bone development in the oral and maxillofacial region [130,131]. Recent interesting evidence suggests that BMP9 has the odontogenic potential [132,133]. As a result, future studies should further discuss the underlying mechanism of BMP9-induced odontogenesis at the molecular level, which could serve as the biological foundation for advanced tissue engineering in future oral and maxillofacial surgeries.

Perspectives

  • The importance of the field: The repair of complicated bone defects and some surgical techniques, such as implantation, is complicated if the insufficient bone volume is regenerated. Insufficient bone volume in patients is often seen in cases of fracture nonunion, delayed union, or complications during specific surgical procedures, resulting in physical and emotional burdens. The potential therapeutic value of BMP9 is high in patients with an urgent need to increase bone volume. To further develop the functional roles of BMP9 in oral and maxillofacial tissue engineering and bone diseases, it is essential to fully understand the signaling events and epigenetic control of BMP9-induced osteogenesis.

  • Summary of the current thinking: In addition to the widely accepted BMP9/SMAD signaling pathways, a large cross-talk network including the SMAD-independent BMP9, Wnt/β, Hedgehog, EGF, TGF-β and Notch signaling pathways finely regulates osteogenesis induced by BMP9. Epigenetic control during BMP9-induced osteogenesis related to HDACs, miRNAs and lncRNAs has been reported. A composite allogenic approach may become a regular paradigm in most BMP9-related tissue engineering applications, including but not limited to those in oral and maxillofacial surgery.

  • Future directions: Widespread epigenetic regulation of the osteogenic process may provide a new perspective on BMP9 signaling pathways, in which lncRNAs may play a significant role. In addition, more direct mechanisms of interaction must be examined in cross-talk studies. Several studies have reported that BMP9 also has odontogenic potential very similar but not identical with that of BMP-induced osteogenesis, and future studies should elucidate the underlying mechanism of BMP9-induced odontogenesis at the molecular level.

Competing Interests

All authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81900996 [D.Z.S] and 81771063[D.M.H]), and the Postdoc Science Funding of China (2019M653441 [D.Z.S]).

Author Contributions

L.L. took part in the conception of this review and drafted the article. Y.C. drafted the article and drew schematic figures. D.Z.S. and D.M.H. guided this project, critically revised the article for important intellectual content and performed the final approval of the version to be submitted.

Abbreviations

     
  • ActR

    antibody-coupled T cell receptor

  •  
  • ADSCs

    adipose-derived stem cells

  •  
  • Akt

    protein kinase B

  •  
  • ALP

    alkaline phosphatase

  •  
  • APC

    adenomatous polyposis coli

  •  
  • AXIN

    axis inhibition protein

  •  
  • BMAC

    bone marrow aspirate concentrate

  •  
  • BMP

    bone morphogenetic protein

  •  
  • BMPR

    bone morphogenetic protein receptor

  •  
  • CBP

    CREB-binding protein

  •  
  • ceRNA

    competing endogenous RNA

  •  
  • ChIP

    chromatin immunoprecipitation

  •  
  • CK1

    casein kinase 1

  •  
  • cKO

    conditional knockout

  •  
  • CSL

    centromere binding factor-1 (in humans)

  •  
  • CV2

    crossveinless 2

  •  
  • Dkk1

    Dickkopf-1

  •  
  • DLL1

    delta (drosophila)-like 1

  •  
  • Dlx5

    distal-less homeobox 5

  •  
  • DME

    DNA demethylase

  •  
  • dnALK2

    dominant-negative ALK2

  •  
  • DNMT

    DNA methyltransferase

  •  
  • dnNotch1

    dominant-negative Notch1

  •  
  • Dvl

    disheveled

  •  
  • EGF

    epidermal growth factor

  •  
  • EGFL7

    epidermal growth factor-like domain 7

  •  
  • ERK

    extracellular signal-regulated kinase

  •  
  • FAK

    focal adhesion kinase

  •  
  • FAK

    focal adhesion kinase

  •  
  • GBR

    guided bone regeneration

  •  
  • GDF2

    Growth differentiation factor 2

  •  
  • Gli

    glioma-associated oncogene homolog

  •  
  • GSK3-β

    glycogen synthase kinase 3-β

  •  
  • HAT

    histone acetyltransferase

  •  
  • HDAC

    histone deacetylase

  •  
  • HDM

    histone demethylase

  •  
  • HEK-293 cell

    human embryonic kidney 293 cell

  •  
  • HIF1α

    hypoxia-inducible factors 1α

  •  
  • iMAD

    immortalized mouse adipocyte-derived mesenchymal stem cell

  •  
  • lncRNA

    long noncoding RNA

  •  
  • LRP

    lipoprotein receptor-related protein

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MEFs

    mouse embryonic fibroblasts

  •  
  • Mek

    MAPK/ERK kinase

  •  
  • miRNA

    microRNA

  •  
  • MKK

    MAPK pathway member-encoding genes kinase

  •  
  • MSCs

    mesenchymal stem cells

  •  
  • NICD

    Notch intracellular domain

  •  
  • OC

    osteocalcin

  •  
  • Osx

    osterix

  •  
  • PPCNg

    polydiolcitrate-gelatin

  •  
  • PRF

    platelet-rich fibrin

  •  
  • PRP

    platelet-rich plasma

  •  
  • PS

    presenilin

  •  
  • Ptch receptor

    patched receptor

  •  
  • rhBMP

    recombinant human BMP

  •  
  • RUNX2

    runt-related transcription factor 2

  •  
  • SBE

    SMAD binding element

  •  
  • Smo

    7-membrane-spanning receptor-like protein Smoothened

  •  
  • SMSCs

    synovial mesenchymal stem cells

  •  
  • Sost

    sclerostin

  •  
  • SUMO

    small ubiquitin-related modifier

  •  
  • TAB1

    TAK1-binding protein 1

  •  
  • TAK1

    transforming growth factor-beta-activated kinase-1

  •  
  • TF

    transcription factor

  •  
  • TGF

    transforming growth factor

  •  
  • TPA

    12-O-tetradecanoylphorbol-13-acetate

  •  
  • Ubc9

    ubiquitin-conjugating enzyme 9

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