Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

BK Channel Deficiency in Osteoblasts Reduces Bone Formation via the Wnt/β-Catenin Pathway

  • Jiang, Lan (Department of Pharmacology, School of Pharmacy & Minhang Hospital, Fudan University) ;
  • Yang, Qianhong (Department of Pharmacology, School of Pharmacy & Minhang Hospital, Fudan University) ;
  • Gao, Jianjun (Department of Bone Metabolism, Institute of Radiation Medicine, Fudan University) ;
  • Yang, Jiahong (Department of Pharmacology, School of Pharmacy & Minhang Hospital, Fudan University) ;
  • He, Jiaqi (Department of Pharmacology, School of Pharmacy & Minhang Hospital, Fudan University) ;
  • Xin, Hong (Department of Pharmacology, School of Pharmacy & Minhang Hospital, Fudan University) ;
  • Zhang, Xuemei (Department of Pharmacology, School of Pharmacy & Minhang Hospital, Fudan University)
  • Received : 2021.01.07
  • Accepted : 2021.06.13
  • Published : 2021.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

Global knockout of the BK channel has been proven to affect bone formation; however, whether it directly affects osteoblast differentiation and the mechanism are elusive. In the current study, we further investigated the role of BK channels in bone development and explored whether BK channels impacted the differentiation and proliferation of osteoblasts via the canonical Wnt signaling pathway. Our findings demonstrated that knockout of Kcnma1 disrupted the osteogenesis of osteoblasts and inhibited the stabilization of β-catenin. Western blot analysis showed that the protein levels of Axin1 and USP7 increased when Kcnma1 was deficient. Together, this study confirmed that BK ablation decreased bone mass via the Wnt/β-catenin signaling pathway. Our findings also showed that USP7 might have the ability to stabilize the activity of Axin1, which would increase the degradation of β-catenin in osteoblasts.

Keywords

Acknowledgement

This work was supported by grants from the National Natural Science Foundation of China (No. 81773801), the Experimental Animal Project of Shanghai Science and Technology Commission (No. 201409004700), Shanghai Municipal Health Commission grants (No. 202040105), and Clinical Research Plan of SHCD.

References

  1. Alula, K., Delgado-Deida, Y., Jackson, D., Venuprasad, K., and Theiss, A. (2021). Nuclear partitioning of Prohibitin 1 inhibits Wnt/β-catenin-dependent intestinal tumorigenesis. Oncogene 40, 369-383. https://doi.org/10.1038/s41388-020-01538-y
  2. An, T., Gong, Y., Li, X., Kong, L., Ma, P., Gong, L., Zhu, H., Yu, C., Liu, J., Zhou, H., et al. (2017). USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth. Biochem. Pharmacol. 131, 29-39. https://doi.org/10.1016/j.bcp.2017.02.011
  3. Appelman-Dijkstra, N.M. and Papapoulos, S.E. (2018). Clinical advantages and disadvantages of anabolic bone therapies targeting the WNT pathway. Nat. Rev. Endocrinol. 14, 605-623. https://doi.org/10.1038/s41574-018-0087-0
  4. Bailey, C.S., Moldenhauer, H.J., Park, S.M., Keros, S., and Meredith, A.L. (2019). KCNMA1-linked channelopathy. J. Gen. Physiol. 151, 1173-1189. https://doi.org/10.1085/jgp.201912457
  5. Bhattacharya, S., Chakraborty, D., Basu, M., and Ghosh, M.K. (2018). Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases. Signal Transduct. Target. Ther. 3, 17. https://doi.org/10.1038/s41392-018-0012-y
  6. Bian, S., Bai, J., Chapin, H., Moellic, C.L., Dong, H., Caplan, M., Sigworth, F.J., and Navaratnam, D.S. (2011). Interactions between β-catenin and the HSlo potassium channel regulates HSlo surface expression. PLoS One 6, e28264. https://doi.org/10.1371/journal.pone.0028264
  7. Castillo, J.P., Sanchez-Rodriguez, J.E., Hyde, H.C., Zaelzer, C.A., Aguayo, D., Sepulveda, R.V., Luk, L.Y., Kent, S.B., Gonzalez-Nilo, F.D., Bezanilla, F., et al. (2016). β1-subunit-induced structural rearrangements of the Ca2+- and voltage-activated K+ (BK) channel. Proc. Natl. Acad. Sci. U. S. A. 113, E3231-E3239. https://doi.org/10.1073/pnas.1606381113
  8. Chen, X., Wang, Z., Duan, N., Zhu, G., Schwarz, E., and Xie, C. (2018). Osteoblast-osteoclast interactions. Connect. Tissue Res. 59, 99-107. https://doi.org/10.1080/03008207.2017.1290085
  9. Choi, J., Lai, J., Xiong, Z., Ren, M., Moorer, M., Stains, J., and Cao, K. (2018). Diminished canonical β-catenin signaling during osteoblast differentiation contributes to osteopenia in progeria. J. Bone Miner. Res. 33, 2059-2070. https://doi.org/10.1002/jbmr.3549
  10. Foller, M., Jaumann, M., Dettling, J., Saxena, A., Pakladok, T., Munoz, C., Ruth, P., Sopjani, M., Seebohm, G., Ruttiger, L., et al. (2012). AMP-activated protein kinase in BK-channel regulation and protection against hearing loss following acoustic overstimulation. FASEB J. 26, 4243-4253. https://doi.org/10.1096/fj.12-208132
  11. Friese, A., Kapoor, S., Schneidewind, T., Vidadala, S., Sardana, J., Brause, A., Forster, T., Bischoff, M., Wagner, J., Janning, P., et al. (2019). Chemical genetics reveals a role of dCTP pyrophosphatase 1 in Wnt signaling. Angew. Chem. Int. Ed. Engl. 58, 13009-13013. https://doi.org/10.1002/anie.201905977
  12. Funato, N., Taga, Y., Laurie, L., Tometsuka, C., Kusubata, M., and Ogawa-Goto, K. (2020). The transcription factor HAND1 is involved in cortical bone mass through the regulation of collagen expression. Int. J. Mol. Sci. 21, 8638. https://doi.org/10.3390/ijms21228638
  13. Gonzalez-Perez, V. and Lingle, C.J. (2019). Regulation of BK channels by beta and gamma subunits. Annu. Rev. Physiol. 81, 113-137. https://doi.org/10.1146/annurev-physiol-022516-034038
  14. Hei, H., Gao, J., Dong, J., Tao, J., Tian, L., Pan, W., Wang, H., and Zhang, X. (2016). BK knockout by TALEN-mediated gene targeting in osteoblasts: KCNMA1 determines the proliferation and differentiation of osteoblasts. Mol. Cells 39, 530-535. https://doi.org/10.14348/molcells.2016.0033
  15. Henney, N.C., Li, B., Elford, C., Reviriego, P., Campbell, A.K., Wann, K.T., and Evans, B.A. (2009). A large-conductance (BK) potassium channel subtype affects both growth and mineralization of human osteoblasts. Am. J. Physiol. Cell Physiol. 297, C1397-C1408. https://doi.org/10.1152/ajpcell.00311.2009
  16. Hirukawa, K., Muraki, K., Ohya, S., Imaizumi, Y., and Togari, A. (2008). Electrophysiological properties of a novel Ca(2+)-activated K(+) channel expressed in human osteoblasts. Calcif. Tissue Int. 83, 222-229. https://doi.org/10.1007/s00223-008-9167-9
  17. Hu, Y., Hao, X., Liu, C., Ren, C., Wang, S., Yan, G., Meng, Y., Mishina, Y., Shi, C., and Sun, H. (2021). Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL-induced osteoclastogenesis. J. Cell. Physiol. 236, 4580-4591. https://doi.org/10.1002/jcp.30183
  18. Ji, L., Lu, B., Zamponi, R., Charlat, O., Aversa, R., Yang, Z., Sigoillot, F., Zhu, X., Hu, T., Reece-Hoyes, J., et al. (2019). USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin. Nat. Commun. 10, 4184. https://doi.org/10.1038/s41467-019-12143-3
  19. Kim, R. and Sixma, T. (2017). Regulation of USP7: a high incidence of E3 complexes. J. Mol. Biol. 429, 3395-3408. https://doi.org/10.1016/j.jmb.2017.05.028
  20. Kwan, B.C., Chow, K., Leung, C., Law, M., Cheng, P.M., Yu, V., Li, P.K., and Szeto, C. (2013). Circulating bacterial-derived DNA fragments as a marker of systemic inflammation in peritoneal dialysis. Nephrol. Dial. Transplant. 28, 2139-2145. https://doi.org/10.1093/ndt/gft100
  21. Lesage, F., Hibino, H., and Hudspeth, A.J. (2004). Association of beta-catenin with the alpha-subunit of neuronal large-conductance Ca2+-activated K+ channels. Proc. Natl. Acad. Sci. U. S. A. 101, 671-675. https://doi.org/10.1073/pnas.0307681100
  22. Li, M., Sun, Y., Simard, J., Wang, J., and Chai, T.C. (2009). Augmented bladder urothelial polyamine signaling and block of BK channel in the pathophysiology of overactive bladder syndrome. Am. J. Physiol. Cell Physiol. 297, C1445-C1451. https://doi.org/10.1152/ajpcell.00259.2009
  23. Li, V., Ng, S., Boersema, P., Low, T., Karthaus, W., Gerlach, J., Mohammed, S., Heck, A., Maurice, M., Mahmoudi, T., et al. (2012). Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell 149, 1245-1256. https://doi.org/10.1016/j.cell.2012.05.002
  24. Marie, P. (2008). Transcription factors controlling osteoblastogenesis. Arch. Biochem. Biophys. 473, 98-105. https://doi.org/10.1016/j.abb.2008.02.030
  25. Matsumoto, Y., Rose, J.L., Lim, M., Adissu, H.A., Law, N., Mao, X., Cong, F., Mera, P., Karsenty, G., Goltzman, D., et al. (2017). Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism. J. Clin. Invest. 127, 2612-2625. https://doi.org/10.1172/JCI92233
  26. Matsushita, Y., Nagata, M., Kozloff, K.M., Welch, J.D., Mizuhashi, K., Tokavanich, N., Hallett, S.A., Link, D.C., Nagasawa, T., Ono, W., et al. (2020). A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. Nat. Commun. 11, 332. https://doi.org/10.1038/s41467-019-14029-w
  27. Nakashima, K., Zhou, X., Kunkel, G., Zhang, Z., Deng, J., Behringer, R., and de Crombrugghe, B. (2002). The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17-29. https://doi.org/10.1016/S0092-8674(01)00622-5
  28. Niday, Z. and Bean, B.P. (2021). BK channel regulation of after-potentials and burst firing in cerebellar Purkinje neurons. J. Neurosci. 41, 2854-2869. https://doi.org/10.1523/JNEUROSCI.0192-20.2021
  29. Oh, Y., Ahn, C., and Je, J. (2020). Blue mussel-derived peptides PIISVYWK and FSVVPSPK trigger Wnt/±-catenin signaling-mediated osteogenesis in human bone marrow mesenchymal stem cells. Mar. Drugs 18, 510. https://doi.org/10.3390/md18100510
  30. Park, H., Kim, J., and Baek, K. (2020). Regulation of Wnt signaling through ubiquitination and deubiquitination in cancers. Int. J. Mol. Sci. 21, 3904. https://doi.org/10.3390/ijms21113904
  31. Qian, L., Liu, X., Yu, Z., and Wang, R. (2020). BK channel dysfunction in diabetic coronary artery: role of the E3 ubiquitin ligases. Front. Physiol. 11, 453. https://doi.org/10.3389/fphys.2020.00453
  32. Qing, H. and Bonewald, L.F. (2009). Osteocyte remodeling of the perilacunar and pericanalicular matrix. Int. J. Oral Sci. 1, 59-65. https://doi.org/10.4248/ijos.09019
  33. Rezzonico, R., Cayatte, C., Bourget-Ponzio, I., Romey, G., Belhacene, N., Loubat, A., Rocchi, S., Obberghen, E.V., Girault, J., Rossi, B., et al. (2003). Focal adhesion kinase pp125FAK interacts with the large conductance calcium-activated hSlo potassium channel in human osteoblasts: potential role in mechanotransduction. J. Bone Miner. Res. 18, 1863-1871. https://doi.org/10.1359/jbmr.2003.18.10.1863
  34. Saidak, Z., Le Henaff, C., Azzi, S., Marty, C., Da Nascimento, S., Sonnet, P., and Marie, P. (2015). Wnt/β-catenin signaling mediates osteoblast differentiation triggered by peptide-induced α5β1 integrin priming in mesenchymal skeletal cells. J. Biol. Chem. 290, 6903-6912. https://doi.org/10.1074/jbc.M114.621219
  35. Sausbier, U., Dullin, C., Missbach-Guentner, J., Kabagema, C., Flockerzie, K., Kuscher, G.M., Stuehmer, W., Neuhuber, W., Ruth, P., Alves, F., et al. (2011). Osteopenia due to enhanced cathepsin K release by BK channel ablation in osteoclasts. PLoS One 6, e21168. https://doi.org/10.1371/journal.pone.0021168
  36. Schickling, B.M., England, S.K., Aykin-Burns, N., Norian, L.A., Leslie, K.K., and Frieden-Korovkina, V.P. (2015). BKCa channel inhibitor modulates the tumorigenic ability of hormone-independent breast cancer cells via the Wnt pathway. Oncol. Rep. 33, 533-538. https://doi.org/10.3892/or.2014.3617
  37. Shu, B., Zhao, Y., Zhao, S., Pan, H., Xie, R., Yi, D., Lu, K., Yang, J., Xue, C., Huang, J., et al. (2020). Inhibition of Axin1 in osteoblast precursor cells leads to defects in postnatal bone growth through suppressing osteoclast formation. Bone Res. 8, 31. https://doi.org/10.1038/s41413-020-0104-5
  38. Song, D., He, G., Song, F., Wang, Z., Liu, X., Liao, L., Ni, J., Silva, M., and Long, F. (2020). Inducible expression of Wnt7b promotes bone formation in aged mice and enhances fracture healing. Bone Res. 8, 4. https://doi.org/10.1038/s41413-019-0081-8
  39. Typlt, M., Mirkowski, M., Azzopardi, E., Ruettiger, L., Ruth, P., and Schmid, S. (2013). Mice with deficient BK channel function show impaired prepulse inhibition and spatial learning, but normal working and spatial reference memory. PLoS One 8, e81270. https://doi.org/10.1371/journal.pone.0081270
  40. Wang, F., Rummukainen, P., Heino, T., and Kiviranta, R. (2021). Osteoblastic Wnt1 regulates periosteal bone formation in adult mice. Bone 143, 115754. https://doi.org/10.1016/j.bone.2020.115754
  41. Wang, Z., Subramanya, A., Satlin, L., Pastor-Soler, N., Carattino, M., and Kleyman, T. (2013). Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase. Am. J. Physiol. Cell Physiol. 305, C846-C853. https://doi.org/10.1152/ajpcell.00133.2013
  42. Whitt, J., McNally, B., and Meredith, A.L. (2018). Differential contribution of Ca2+ sources to day and night BK current activation in the circadian clock. J. Gen. Physiol. 150, 259-275. https://doi.org/10.1085/jgp.201711945
  43. Xiang, L., Zheng, J., Zhang, M., Ai, T., and Cai, B. (2020). FOXQ1 promotes the osteogenic differentiation of bone mesenchymal stem cells via Wnt/β-catenin signaling by binding with ANXA2. Stem Cell Res. Ther. 11, 403. https://doi.org/10.1186/s13287-020-01928-9
  44. Zhang, L., Tang, Y., Zhu, X., Tu, T., Sui, L., Han, Q., Yu, L., Meng, S., Zheng, L., Valverde, P., et al. (2017). Overexpression of miR-335-5p promotes bone formation and regeneration in mice. J. Bone Miner. Res. 32, 2466-2475. https://doi.org/10.1002/jbmr.3230
  45. Zhang, X., Wang, Y., Zhao, H., Han, X., Zhao, T., Qu, P., Li, G., and Wang, W. (2020). Extracellular vesicle-encapsulated miR-22-3p from bone marrow mesenchymal stem cell promotes osteogenic differentiation via FTO inhibition. Stem Cell Res. Ther. 11, 227. https://doi.org/10.1186/s13287-020-01707-6
  46. Zhang, Y., Liu, S., Mickanin, C., Feng, Y., Charlat, O., Michaud, G., Schirle, M., Shi, X., Hild, M., Bauer, A., et al. (2011). RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat. Cell Biol. 13, 623-629. https://doi.org/10.1038/ncb2222
  47. Zhang, Y., Yue, J., Che, H., Sun, H., Tse, H., and Li, G. (2014). BKCa and hEag1 channels regulate cell proliferation and differentiation in human bone marrow-derived mesenchymal stem cells. J. Cell. Physiol. 229, 202-212. https://doi.org/10.1002/jcp.24435
  48. Zhou, L., Huang, Y., Zhao, J., Yang, H., and Kuai, F. (2020). Oridonin promotes osteogenesis through Wnt/β-catenin pathway and inhibits RANKL-induced osteoclastogenesis in vitro. Life Sci. 262, 118563. https://doi.org/10.1016/j.lfs.2020.118563