**10. miRNA regulation in bone resorption**

miRNAs not only regulates the osteoblastogenesis but also sustains the bone disruptive processes by acting on the genes or proteins partaking in the signaling pathways that are functional inside the osteoclast (**Table 3**). Understanding the miRNA mediated regulation of osteoclastic differentiation will highlight the mechanism behind the differentiation process for the osteoclasts in the bone [84]. Initiating signal (binding of RANKL to the receptors) stimulates various downstream pathways (PI3K, NFK-β, MAPK) that on activation of distinct transcription factors (c-Fos, NFATc1, PU.1) control the osteoclast differentiation [84].


*PBMC, peripheral blood mononuclear cells; Calcr, calcitonin receptor; CXCL12, C-X-C motif chemokine 12; MITF, microphthalmia-associated transcription factor; PDCD4, programmed cell death protein 4; MAFB, MAF BZIP transcription factor B.*

#### **Table 3.**

*Clinical Implementation of Bone Regeneration and Maintenance*

duplex in the cytoplasm.

lated apoptosis in the cells [68].

e.RNase III enzyme called Dicer slices the pre-miRNA into miRNA-miRNA

f. The Dicer mediated cleavage is usually associated with the unwinding of miRNA duplex wherein one miRNA strand (guide strand) is selected to be incorporated in the RISC (RNA induced silencing complex), and the other miRNA strand (passenger strand) is frequently degraded. The RISC contains

g.Argonaute proteins generally interact with the mature miRNA and prepare it in

h.Perfect base pairing between the miRNA and cognate mRNA leads to degradation of the target mRNA while imperfect or partial complementarity usually

Most often, miRNA binds to 3′UTR regions of the genes and executes its action. miRNAs are generally regarded as post-transcriptional regulators that check the process of proliferation, apoptosis, differentiation and development [64]. Several miRNAs are documented to regulate the process of osteogenic proliferation, such as excessive expression of miR-221 and miR-215 in the mouse osteoblast cells encourages the proliferative capacity of the cells [65, 66]. Likewise, downregulation of miR-185 results in the declined osteoblast proliferation [67]. Besides, increased expression of miR-495 in osteoblasts results in diminished proliferation and stimu-

Differentiation of the osteoblast cells is an essential facet for the development of the adult skeleton. Most importantly, miRNAs have great potential to act against

**miRNA Target gene Targeted signaling pathway Reference** miR-433-3p DKK1 Wnt/β-catenin [69] miR-208a-3p ACVR1 BMP [70] miR-1187 BMPR2 BMP2 [71] miR-29a Histone deacetylase 4 β-catenin [72] miR-590-5p Smad7 BMP-Smad-Runx2 [73] miR-450b BMP-3 BMP [74] miR-135 Smad5 BMP-Smad [75] miR-34c Notch1 Delta-Notch [76] miR-224 Smad4 BMP-Smad [77] miR-21 HIF-1α PTEN/PI3K/Akt [78]

*Role of miRNAs in the osteogenic differentiation by acting on various components in the bone signaling* 

Dicer, miRNA, argonaute and other accessory proteins.

results in the suppression at the protein level.

**8. miRNA regulation in osteoblast proliferation**

**9. miRNA regulation in osteoblast differentiation**

the correct orientation for the subsequent binding with mRNA.

**218**

**Table 2.**

*pathways.*

*Representation of a few examples where miRNAs have played a vital role in the bone resorption.*
