A microRNA expression signature of osteoclastogenesis

Abstract

IntroductionThe osteoclast, the exclusive bone resorptive cell, is derived from hematopoietic stem cells through the common myeloid progenitor to the colony-forming unit for granulocytes and macrophages to the colony-forming unit for macrophages and into the osteoclast lineage. 1 Osteoclast differentiation, function, and survival are regulated by several exogenous cytokines (macrophage colonystimulating factor [M-CSF], receptor activator of nuclear factor B ligand [RANKL], tumor necrosis factor ␣, interleukin-1, and interleukin-6) and hormones (sex steroids, parathyroid hormone, vitamin D, insulinlike growth factor-1, calcitonin, and prostaglandins) through several transcription factors activities identified by studies in genetically engineered mice. 2,3 The transcription factor c-Fos plays an important role in osteoclastogenesis because mice lacking c-Fos develop osteopetrosis. 2-4 c-Fos is not required for normal osteoprogenitor development but is required for osteoclastogenesis. [2][3][4] Nuclear factor of activated T cells cytoplasmic 1 (NFATc1) is also a critical transcription factor that was discovered as an early RANKL-inducible gene by gene expression profiling after RANKL stimulation. 3 NFATc1 molecules act as cofactors with activator protein-1 (AP-1) composed of Fos/Jun proteins to bind to regulatory cis DNA elements, 5 and osteoclastspecific markers such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K have multiple sites recognized by NFATc1 as well as its partner AP-1. 5 MicroRNAs (miRs), which regulate gene expression, are transcribed as primary miRs (pri-miRs) containing a 5Ј-cap structure and poly(A) tail that are processed to produce the mature miRs. 6 Two nuclease enzymes, the nuclear RNaseIII Drosha and the cytosolic RNaseIII Dicer, are known to act sequentially to trim the miRs to mature form. 6 Hundreds of miR genes have been identified in the human genome, and it is estimated that one-third of protein-coding genes are regulated by miRs. Hence, miRs constitute one of the most abundant classes of gene-regulatory molecules in animals, and they are implicated in almost every biologic process, including development timing, cell differentiation, cell proliferation, cell death, metabolic control, transposon silencing, and antiviral defense. 6 Emerging evidence indicates that Dicer-generated miRs play important roles in osteoblastogenesis, chondrocyte proliferation and differentiation, and osteoclastogenesis. [7][8][9][10] Recent studies have shown that Ն 12 miRs, miR-26a, miR-125b, miR-133, miR-135, miR-29a, miR-141, miR-200a, miR-210, miR-29, miR-378, miR-2861, and miR-206, are implicated in osteoblast differentiation. [11][12][13][14][15][16][17][18][19][20] In particular, miR-2861 was identified as a novel miR expressed in mouse osteoblasts promoting osteoblast differentiation by suppressing expression of histone deacetylase 5 at the posttranslational level and contributing to bone formation. 19 Moreover, mutation of miR-2861 causes osteoporosis in humans, suggesting that miR-2861...

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

“…(64) Other miRNAs, such as miR-21 and miR-378, have been implicated in osteoclastogenesis. (65) In particular, miR-21 is of interest because miR-21 is not only known as "inflamma-miR," (66) but has been shown to mediate RANKL-induced osteoclast differentiation (67) and inhibit osteoclast apoptosis. (68) Given that we found significantly higher serum miR-21 serum levels in DMFx than in DM subjects and that DMFx were described to have more cortical porosity, (29) osteoclast dysfunction/or prolonged osteoclast survival might be a potential mechanisms that could explain the higher fracture risk in the DMFx patients.…”

MicroRNAs as regulators of bone homeostasis and bone metastasis

“…7 Cultured bone marrow from these mice was incapable of producing osteoclasts ex vivo, further confirming the defect in osteoclast maturation. 8,9 Importantly, this defect was not confined to Dicer; knockdown of DGCR8 and Ago2 using siRNA similarly resulted in decreased osteoclast differentiation and bone resorption, and osteoclastspecific DGCR8 knockout mice display impaired bone development. 7,10 Taken together, these results reveal the necessity for proper miRNA regulation during the differentiation and maintenance of multiple essential cell types required for bone homeostasis.…”

miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B

“…(5)(6)(7)(8)(9) miR-21 regulates osteoclastogenesis of bone marrow-derived monocyte/macrophage precursors (BMMs) via targeting programmed cell death protein 4 (PDCD4). (5) miR-223 expresses in the RAW264.7 osteoclast precursor cell line and controls osteoclast differentiation by regulating nuclear factor I-A (NFI-A) and the macrophage colony-stimulating factor receptor (M-CSFR) levels. (6) In contrast, Mann and colleagues (7) found that miR-155 was downregulated in osteoclasts and upregulated in macrophages.…”