Ninjurin1 positively regulates osteoclast development by enhancing the survival of prefusion osteoclasts

다국어 초록 (Multilingual Abstract)

Osteoclasts (OCs) are bone-resorbing cells that originate from hematopoietic stem cells and develop through the fusion of mononuclear myeloid precursors. Dysregulation of OC development causes bone disorders such as osteopetrosis, osteoporosis, and rheumatoid arthritis. Although the molecular mechanisms underlying osteoclastogenesis have been well established, the means by which OCs maintain their survival during OC development remain unknown. We found that Ninjurin1 (Ninj1) expression is dynamically regulated during osteoclastogenesis and that Ninj1−/− mice exhibit increased trabecular bone volume owing to impaired OC development. Ninj1 deficiency did not alter OC differentiation, transmigration, fusion, or actin ring formation but increased Caspase-9-dependent intrinsic apoptosis in prefusion OCs (preOCs). Overexpression of Ninj1 enhanced the survival of mouse macrophage/preOC RAW264.7 cells in osteoclastogenic culture, suggesting that Ninj1 is important for the survival of preOCs. Finally, analysis of publicly available microarray data sets revealed a potent correlation between high NINJ1 expression and destructive bone disorders in humans. Our data indicate that Ninj1 plays an important role in bone homeostasis by enhancing the survival of preOCs.

참고문헌 (Reference)

1 Lee S. H., "v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation" 12 : 1403-1409, 2006

2 Loayza-Puch, F., "p53 induces transcriptional and translational programs to suppress cell proliferation and growth" 14 : R32-, 2013

3 Wang, X., "p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling" 172 : 115-125, 2006

4 Park, K. H., "Zinc inhibits osteoclast differentiation by suppression of Ca 2+-Calcineurin-NFATc1 signaling pathway" 11 : 74-, 2013

5 Fujita, K., "Vitamin E decreases bone mass by stimulating osteoclast fusion" 18 : 589-594, 2012

6 Saltel, F., "Transmigration : a new property of mature multinucleated osteoclasts" 21 : 1913-1923, 2006

7 Sharma, N. K., "Tissue-specific and genetic regulation of insulin sensitivityassociated transcripts in African Americans" 101 : 1455-1468, 2016

8 Takayanagi, H., "The role of NFAT in osteoclast formation" 1116 : 227-237, 2007

9 Teitelbaum, S. L., "The osteoclast and its unique cytoskeleton" 1240 : 14-17, 2011

10 Asagiri, M., "The molecular understanding of osteoclast differentiation" 40 : 251-264, 2007

11 Layfield, R., "The molecular pathogenesis of Paget disease of bone" 9 : 1-13, 2007

12 Dai, X. -M., "Targeted disruption of the mouse colony-stimulating factor 1receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects" 99 : 111-120, 2002

13 Glantschnig, H., "TNFαand RANK ligand promote osteoclast survival by signaling through mTOR/S6kinase" 10 : 1165-1177, 2003

14 Watanabe, C., "Stability of mRNA influences osteoporotic bone mass via CNOT3" 111 : 2692-2697, 2014

15 Lee, Z. H., "Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts" 305 : 211-214, 2003

16 Mollazadeh, S., "Role of apoptosis in pathogenesis and treatment of bone-related diseases" 10 : 15-, 2015

17 Ifergan, I., "Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions" 70 : 751-763, 2011

18 Nakamura, I., "Regulation of osteoclast function" 22 : 167-177, 2012

19 Oursler, M. J., "Recent advances in understanding the mechanisms of osteoclast precursor fusion" 110 : 1058-1062, 2010

20 Li, J., "RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism" 97 : 1566-1571, 2000

21 Dougall, W. C., "RANK is essential for osteoclast and lymph node development" 13 : 2412-2424, 1999

22 Braun, T., "Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis" 13 : 235-, 2011

23 Song, R., "P53 suppresses cell proliferation, metastasis, and angiogenesis of osteosarcoma through inhibition of the PI3K/AKT/mTOR pathway" 20 : 80-87, 2015

24 Sobacchi, C., "Osteopetrosis : genetics, treatment and new insights into osteoclast function" 9 : 522-536, 2013

25 Teitelbaum, S. L., "Osteoclasts: what do they do and how do they do it?" 170 : 427-435, 2007

26 Sato, K., "Osteoclasts, rheumatoid arthritis, and osteoimmunology" 18 : 419-426, 2006

27 Xing, L., "Osteoclast fusion and regulation by RANKLdependent and independent factors" 3 : 212-222, 2012

28 Boyle, W. J., "Osteoclast differentiation and activation" 423 : 337-342, 2003

29 Roux, S., "Osteoclast apoptosis in rheumatic diseases characterized by a high level of bone resorption(osteoporosis, rheumatoid arthritis, myeloma and Paget’s disease of bone)" 5 : 98-110, 2009

30 Makras, P., "Novel therapies for osteoporosis" 64 : 1199-1214, 2015

31 Cho, S. J., "Ninjurin1, a target ofp53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality" 110 : 9362-9367, 2013

32 Shin, M. W., "Ninjurin1 regulates lipopolysaccharide-induced inflammation through direct binding" 48 : 821-828, 2016

33 Lee, H. J., "Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development" 16 : 1395-1407, 2009

34 Ahn, B. J., "Ninjurin1 enhances the basal motility and transendothelial migration of immune cells by inducing protrusive membrane dynamics" 289 : 21926-21936, 2014

35 Ahn, B. J., "Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice" 289 : 3328-3338, 2014

36 Bae, S. J., "Ninjurin1 assembles into a homomeric protein complex maintained by N-linked glycosylation" 118 : 2219-2230, 2017

37 Araki, T., "Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth" 17 : 353-361, 1996

38 Yang, H. J., "Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner" 114 : 11500-11505, 2017

39 Zhao, Q., "NFATc1 : functions in osteoclasts" 42 : 576-579, 2010

40 Vignery, A., "Macrophage fusion : the making of osteoclasts and giant cells" 202 : 337-340, 2005

41 Peng, J., "Low bone turnover and reduced angiogenesis in streptozotocininduced osteoporotic mice" 57 : 277-289, 2016

42 Garrido, C., "Life’s smile, death’s grin : vital functions of apoptosisexecuting proteins" 16 : 639-646, 2004

43 Yin, G. N., "Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse" 111 : E2731-E2740, 2014

44 Yagi, M., "Induction of DC-STAMP by alternative activation and downstream signaling mechanisms" 22 : 992-1001, 2007

45 Mochizuki, A., "Identification and characterization of the precursors committed to osteoclasts induced by tnf-related activation-induced cytokine/receptor activator of NF-B ligand" 177 : 4360-4368, 2006

46 Del Fattore, A., "Genetics, pathogenesis and complications of osteopetrosis" 42 : 19-29, 2008

47 Pacifici, R., "Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis" 11 : 1043-1051, 1996

48 Charatcharoenwitthaya, N., "Effect of blockade of TNF-α and interleukin-1 action on bone resorption in early postmenopausal women" 22 : 724-729, 2007

49 Vestergaard, P., "Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes–a meta-analysis" 18 : 427-444, 2007

50 Yagi, M., "DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells" 202 : 345-351, 2005

51 Zou, W., "Cytoskeletal dysfunction dominates in DAP12-deficient osteoclasts" 123 : 2955-2963, 2010

52 Jennewein, C., "Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation" 53 : 656-663, 2015

53 Yu, M., "Complex regulation of tartrateresistant acid phosphatase (TRAP) expression by interleukin 4 (IL-4): IL-4indirectly suppresses receptor activator of NF-kappaB ligand (RANKL)-mediated TRAP expression but modestly induces its expression directly" 284 : 32968-32979, 2009

54 Arai, F., "Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κB(RANK)receptors" 190 : 1741-1754, 1999

55 Kroemer, G., "Classification of cell death : recommendations of the Nomenclature Committee on Cell Death 2009" 16 : 3-11, 2009

56 Iwasaki, R., "Cell fusion in osteoclasts plays a critical role in controlling bone mass and osteoblastic activity" 377 : 899-904, 2008

57 Long, F., "Building strong bones : molecular regulation of the osteoblast lineage" 13 : 27-38, 2012

58 Whyte, M. P., "Bisphosphonate-induced osteopetrosis : novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases" 23 : 1698-1707, 2008

59 Sugatani, T., "Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors" 280 : 3583-3589, 2005

60 Edwards, J. R., "Advances in osteoclast biology : old findings and new insights from mouse models" 7 : 235-243, 2011

61 Saltel, F., "Actin cytoskeletal organisation in osteoclasts : a model to decipher transmigration and matrix degradation" 87 : 459-468, 2008

62 Qiao, Y., "AP-1 Is a key regulator of proinflammatory cytokine tnfalphamediated triple-negative breast cancer progression" 291 : 5068-5079, 2016

63 Akashi, K., "A clonogenic common myeloid progenitor that gives rise to all myeloid lineages" 404 : 193-197, 2000