Osteoclast biology in bone resorption: a review
What we know about bone resorption has changed a lot in the last few decades. The osteoclast is the only cell to nibble and break down the bone, and in the formation and resorption of bone tissue, osteoclasts play an important role. Once the balance of bone formation and bone loss is out of control, diseases like osteopetrosis and osteoporosis occur. Bone resorption is a unique function of osteoblasts, which are multinucleated cells formed by the fusion of mononuclear progenitor cells of the monocyte/macrophage family. In the formation of osteoclasts, there are two main factors affecting this process, macrophage colony-stimulating factor (M-CSF) and ligand-activated receptor (RANKL) of nuclear factor kappa B (NF-κB). The identification of RANK-RANKL signaling and other classic signaling pathways such as Wnt and Notch, as the major signaling regulation in osteoclast differentiation, was a significant breakthrough in the field of osteoclastogenesis. In this review, we briefly describe the latest knowledge of osteoclast-induced bone resorption and cellular factors that regulate the activity of osteoclasts and cell fusion, for the purpose of understanding osteoclastogenesis and the development of drugs that enhance bone resorption to improve pathological bone diseases.
Laperine O, Blin-Wakkach C, Guicheux J, Beck-Cormier S, Lesclous P. Dendritic-cell-derived osteoclasts: a new game changer in bone-resorption-associated diseases. Drug Discov Today. 2016;21(9):1345-54.
Han Y, You X, Xing W, Zhang Z, Zou W. Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res. 2018 May 24;6:16.
Yang D, Wan Y. Molecular determinants for the polarization of macrophage and osteoclast. Semin Immunopathol. 2019 Sep;41(5):551-563.
Kahn AJ, Simmons DJ. Investigation of cell lineage in bone using a chimaera of chick and quial embryonic tissue. Nature. 1975;258(5533):325-7.
Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, et al. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med. 1999;190(12):1741-54.
Walker DG. Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science. 1975;190(4216):784-5.
Wu L, Luo Z, Liu Y, Jia L, Jiang Y, Du J, et al. Aspirin inhibits RANKL-induced osteoclast differentiation in dendritic cells by suppressing NF-kappaB and NFATc1 activation. Stem Cell Res Ther. 2019;10(1):375.
Tondravi MM, McKercher SR, Anderson K, Erdmann JM, Quiroz M, Maki R, et al. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature. 1997;386(6620):81-4.
Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, et al. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci USA. 1990 Sep;87(18):7260-4.
Monajemi M, Fisk S, Pang YCF, Leung J, Menzies SC, Ben-Othman R, et al. Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency. J Leukoc Biol. 2019;106(4):863-77.
Mochizuki A, Takami M, Kawawa T, Suzumoto R, Sasaki T, Shiba A, et al. Identification and characterization of the precursors committed to osteoclasts induced by TNF-related activation-induced cytokine/receptor activator of NF-kappa B ligand. J Immunol. 2006 Oct 1;177(7):4360-8.
Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science. 1994;266(5184):443-8.
Hanada R, Hanada T, Sigl V, Schramek D, Penninger JM. RANKL/RANK-beyond bones. J Mol Med (Berl). 2011 Jul;89(7):647-56.
Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA. 2000 Feb 15;97(4):1566-71.
Narducci P, Nicolin V. Differentiation of activated monocytes into osteoclast-like cells on a hydroxyapatite substrate: an in vitro study. Ann Anat. 2009 Oct;191(4):349-55.
Iotsova V, Caamano J, Loy J, Yang Y, Lewin A, Bravo R. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med. 1997 Nov;3(11):1285-9.
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309-19.
Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999 Sep 15;13(18):2412-24.
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315-23.
Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998 May 1;12(9):1260-8.
Whyte MP, Wenkert D, McAlister WH, Novack DV, Nenninger AR, Zhang X, et al. Dysosteosclerosis presents as an "osteoclast-poor" form of osteopetrosis: comprehensive investigation of a 3-year-old girl and literature review. J Bone Miner Res. 2010 Nov;25(11):2527-39.
Lombardi MS, Gillieron C, Berkelaar M, Gabay C. Salt-inducible kinases (SIK) inhibition reduces RANKL-induced osteoclastogenesis. PloS one. 2017;12(10):e0185426.
Taub M. Salt Inducible kinase signaling networks: implications for acute kidney injury and therapeutic potential. Int J Mol Sci. 2019 Jun 30;20(13):3219.
Uehara S, Udagawa N, Kobayashi Y. Regulation of osteoclast function via Rho-Pkn3-c-Src pathways. J Oral Biosci. 2019;61(3):135-40.
Weivoda MM, Ruan M, Hachfeld CM, Pederson L, Howe A, Davey RA, et al. Wnt signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways. J Bone Miner Res. 2019 Aug;34(8):1546-1548.
Yin Y, Ding L, Hou Y, Jiang H, Zhang J, Dai Z, et al. Upregulating MicroRNA-410 or Downregulating wnt-11 increases osteoblasts and reduces osteoclasts to alleviate osteonecrosis of the femoral head. Nanoscale Res Lett. 2019 Dec 18;14(1):383.
Ashley JW, Ahn J, Hankenson KD. Notch signaling promotes osteoclast maturation and resorptive activity. J Cell Biochem. 2015 Nov;116(11):2598-609.
Teitelbaum SL. The osteoclast and its unique cytoskeleton. Ann N Y Acad Sci. 2011 Dec;1240:14-7.
McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, et al. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest. 2000 Feb;105(4):433-40.
Minkin C. Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function. Calcif Tissue Int. 1982;34(3):285-90.
Motyckova G, Weilbaecher KN, Horstmann M, Rieman DJ, Fisher DZ, Fisher DE. Linking osteopetrosis and pycnodysostosis: regulation of cathepsin K expression by the microphthalmia transcription factor family. Proc Natl Acad Sci USA. 2001 May 8;98(10):5798-803.
Ahn SH, Chen Z, Lee J, Lee SW, Min SH, Kim ND, et al. Inhibitory effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-N-1H-Indol-5-Ylacetamid e) on osteoclast differentiation via suppressing cathepsin K expression. Molecules. 2018 Nov 29;23(12):3139.
Soe K, Delaisse JM. Time-lapse reveals that osteoclasts can move across the bone surface while resorbing. J Cell Sci. 2017 Jun 15;130(12):2026-2035.
Soysa NS, Alles N. Osteoclast function and bone-resorbing activity: An overview. Biochem Biophys Res Commun. 2016;476(3):115-20.
Calle Y, Jones GE, Jagger C, Fuller K, Blundell MP, Chow J, et al. WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption. Blood. 2004;103(9):3552-61.
Pereira M, Petretto E, Gordon S, Bassett JHD, Williams GR, Behmoaras J. Common signalling pathways in macrophage and osteoclast multinucleation. J Cell Sci. 2018 Jun 5;131(11):jcs216267.
Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504-8.
Ishii M, Saeki Y. Osteoclast cell fusion: mechanisms and molecules. Mod Rheumatol. 2008;18(3):220-7.
Mbalaviele G, Chen H, Boyce BF, Mundy GR, Yoneda T. The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow. J Clin Invest. 1995 Jun;95(6):2757-65.
Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med. 2005;202(3):345-51.
Verrier S, Hogan A, McKie N, Horton M. ADAM gene expression and regulation during human osteoclast formation. Bone. 2004;35(1):34-46.
Higuchi S, Tabata N, Tajima M, Ito M, Tsurudome M, Sudo A, et al. Induction of human osteoclast-like cells by treatment of blood monocytes with anti-fusion regulatory protein-1/CD98 monoclonal antibodies. J Bone Miner Res. 1998 Jan;13(1):44-9.
Verma SK, Leikina E, Melikov K, Gebert C, Kram V, Young MF, et al. Cell-surface phosphatidylserine regulates osteoclast precursor fusion. J Biol Chem. 2018 Jan 5;293(1):254-270.
Kim HJ, Yoon HJ, Park JW, Che X, Jin X, Choi JY. G protein-coupled receptor 119 is involved in RANKL-induced osteoclast differentiation and fusion. J Cell Physiol. 2019 Jul;234(7):11490-11499.
Narahara H, Sakai E, Yamaguchi Y, Narahara S, Iwatake M, Okamoto K, et al. Actin binding LIM 1 (abLIM1) negatively controls osteoclastogenesis by regulating cell migration and fusion. J Cell Physiol. 2018 Jan;234(1):486-499.
Fukuda T, Takeda S, Xu R, Ochi H, Sunamura S, Sato T, et al. Sema3A regulates bone-mass accrual through sensory innervations. Nature. 2013;497(7450):490-3.
Foger-Samwald U, Dovjak P, Azizi-Semrad U, Kerschan-Schindl K, Pietschmann P. Osteoporosis: pathophysiology and therapeutic options. EXCLI J. 2020;19:1017-37.
Hsu E, Pacifici R. From osteoimmunology to osteomicrobiology: how the microbiota and the immune system regulate bone. Calcif Tissue Int. 2018;102(5):512-21.
Copyright (c) 2020 Chao Fu, Ruyi Shi
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain full copyright to their individual works, and publishing rights without restrictions.
In accordance with the Budapest Open Access Initiative, articles published in STEMedicine are freely available "on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited."
Except where otherwise noted, all content on this website is licensed under a Creative Commons Attribution 4.0 License. This license allows for commercial and non-commercial redistribution as well as modifications of the work as long as attribution is given to the authors and STEMedicine as the original publication source, and a link to the article on the STEMedicine website is provided.