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Review | Open Access

Small-molecule amines: a big role in the regulation of bone homeostasis

Qian Zhang1,2,Jirong Yang1,2,Nan Hu3Juan Liu1Huan Yu4Haobo Pan1,2,5Di Chen4,6( )Changshun Ruan1,2 ( )
Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
University of Chinese Academy of Sciences, Beijing 100049, China
Department of Nephrology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020 Guangdong, China
Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
Shenzhen Healthemes Biotechnology Co., Ltd., Shenzhen 518102, China
Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China

These authors contributed equally: Qian Zhang, Jirong Yang.

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Abstract

Numerous small-molecule amines (SMAs) play critical roles in maintaining bone homeostasis and promoting bone regeneration regardless of whether they are applied as drugs or biomaterials. On the one hand, SMAs promote bone formation or inhibit bone resorption through the regulation of key molecular signaling pathways in osteoblasts/osteoclasts; on the other hand, owing to their alkaline properties as well as their antioxidant and anti-inflammatory features, most SMAs create a favorable microenvironment for bone homeostasis. However, due to a lack of information on their structure/bioactivity and underlying mechanisms of action, certain SMAs cannot be developed into drugs or biomaterials for bone disease treatment. In this review, we thoroughly summarize the current understanding of SMA effects on bone homeostasis, including descriptions of their classifications, biochemical features, recent research advances in bone biology and related regulatory mechanisms in bone regeneration. In addition, we discuss the challenges and prospects of SMA translational research.

References

1

Moller, A. M. J. et al. Aging and menopause reprogram osteoclast precursors for aggressive bone resorption. Bone Res. 8, 27 (2020).

2

Modinger, Y., Loffler, B., Huber-Lang, M. & Ignatius, A. Complement involvement in bone homeostasis and bone disorders. Semin. Immunol. 37, 53–65 (2018).

3

Liao, J., Han, R., Wu, Y. & Qian, Z. Review of a new bone tumor therapy strategy based on bifunctional biomaterials. Bone Res. 9, 18 (2021).

4
Wiese, A. & Pape, H. C. Bone defects caused by high-energy injuries, bone loss, infected nonunions, and nonunions. Orthop. Clin. North Am. 41, 1–4 (2010). table of contents.
5

Zhang, Y., Luo, G. & Yu, X. Cellular communication in bone homeostasis and the related anti-osteoporotic drug development. Curr. Med. Chem. 27, 1151–1169 (2020).

6

Chen, D. et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res. 5, 16044 (2017).

7

Salhotra, A., Shah, H. N., Levi, B. & Longaker, M. T. Mechanisms of bone development and repair. Nat. Rev. Mol. Cell Biol. 21, 696–711 (2020).

8

Chen, H., Senda, T. & Kubo, K. Y. The osteocyte plays multiple roles in bone remodeling and mineral homeostasis. Med. Mol. Morphol. 48, 61–68 (2015).

9

Feng, X. & Teitelbaum, S. L. Osteoclasts: new insights. Bone Res. 1, 11–26 (2013).

10

Walker, D. G. Osteopetrosis cured by temporary parabiosis. Science 180, 875 (1973).

11

Zambonin Zallone, A., Teti, A. & Primavera, M. V. Monocytes from circulating blood fuse in vitro with purified osteoclasts in primary culture. J. Cell Sci. 66, 335–342 (1984).

12

Søe, K. et al. Coordination of fusion and trafficking of pre-osteoclasts at the marrow-bone interface. Calcif. Tissue Int. 105, 430–445 (2019).

13

MacDonald, B. R. et al. Effects of human recombinant CSF-GM and highly purified CSF-1 on the formation of multinucleated cells with osteoclast characteristics in long-term bone marrow cultures. J. Bone Min. Res. 1, 227–233 (1986).

14

Udagawa, N. 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 87, 7260–7264 (1990).

15

Wiktor-Jedrzejczak, W. et al. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc. Natl. Acad. Sci. USA 87, 4828–4832 (1990).

16

Pixley, F. J. & Stanley, E. R. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 14, 628–638 (2004).

17

McDonald, M. M. et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 184, 1–18 (2021).

18

Hardy, R. & Cooper, M. S. Bone loss in inflammatory disorders. J. Endocrinol. 201, 309–320 (2009).

19

Callaway, D. A. & Jiang, J. X. Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. J. Bone Min. Metab. 33, 359–370 (2015).

20

Arnett, T. R. Extracellular pH regulates bone cell function. J. Nutr. 138, 415S–418S (2008).

21
Macielag, M. J. Antibiotic Discovery and Development (eds T. J. Dougherty & M. J. Pucci) 793–819 (Springer New York, NY, 2011).
22

Momeni, A., Rapp, S., Donneys, A., Buchman, S. R. & Wan, D. C. Clinical use of deferoxamine in distraction osteogenesis of irradiated bone. J. Craniofac. Surg. 27, 880–882 (2016).

23

Wang, L. et al. Dopamine suppresses osteoclast differentiation via cAMP/PKA/CREB pathway. Cell Signal. 78, 109847 (2021).

24

Gu, L., Ke, Y., Gan, J. & Li, X. Berberine suppresses bone loss and inflammation in ligature-induced periodontitis through promotion of the G protein-coupled estrogen receptor-mediated inactivation of the p38MAPK/NF-kappaB pathway. Arch. Oral. Biol. 122, 104992–104992 (2020).

25

Wang, L. et al. Tetramethylpyrazine protects against glucocorticoid-induced apoptosis by promoting autophagy in mesenchymal stem cells and improves bone mass in glucocorticoid-induced osteoporosis rats. Stem Cells Dev. 26, 419–430 (2017).

26

Price, P. A., June, H. H., Buckley, J. R. & Williamson, M. K. SB 242784, a selective inhibitor of the osteoclastic V-H + ATPase, inhibits arterial calcification in the rat. Circ. Res. 91, 547–552 (2002).

27

Adam, S. et al. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci. Transl. Med. 12, eaay4447 (2020).

28

Vidal, B. et al. Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model. Rheumatology 57, 1461–1471 (2018).

29

Chandra, A. et al. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. FASEB J. 32, 52–62 (2018).

30

Shaik, A. R. et al. Metformin: is it the well wisher of bone beyond glycemic control in diabetes mellitus? Calcif. Tissue Int. 108, 693–707 (2021).

31

Ma, P. et al. Glimepiride promotes osteogenic differentiation in rat osteoblasts via the PI3K/Akt/eNOS pathway in a high glucose microenvironment. PLoS One 9, e112243 (2014).

32
S. L., Taylor & S. L., Hefle. Foodborne Diseases (eds C. E. R. Dodd et al.) 327–344 (Academic Press, 2017).
33

Zhu, M. P. et al. Vinpocetine inhibits RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss. Biomed. Pharmacother. 123, 10 (2020).

34

Jin, H., Yao, L. & Chen, K. Evodiamine inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in mice. J. Cell. Mol. Med. 23, 4850–4850 (2019).

35

Zeng, X. Z. et al. Aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing NF-kappa B and NFATc1 activation and DC-STAMP expression. Acta Pharmacol. Sin. 37, 255–263 (2016).

36
Ouellette, R. J. & Rawn, J. D. Organic Chemistry (eds R. J. Ouellette & J. David Rawn) 803–842 (Elsevier, 2014).
37

Lovaas, E. Antioxidative and metal-chelating effects of polyamines. Adv. Pharm. 38, 119–149 (1997).

38

Zhou, T., Wang, P., Gu, Z., Ma, M. & Yang, R. Spermidine improves antioxidant activity and energy metabolism in mung bean sprouts. Food Chem. 309, 125759 (2020).

39
Drugbank online. Odanacatib, <https://go.drugbank.com/drugs/DB06670> (2022).
40

Kim, S. H. et al. Bortezomib prevents ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation. J. Bone Min. Metab. 36, 537–546 (2018).

41

de Vries, T. J. et al. The Src inhibitor AZD0530 reversibly inhibits the formation and activity of human osteoclasts. Mol. Cancer Res. 7, 476–488 (2009).

42

Yang, J. C. et al. Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol. Cancer Ther. 9, 1629–1637 (2010).

43

Jiao, H., Xiao, E. & Graves, D. T. Diabetes and its effect on bone and fracture healing. Curr. Osteoporos. Rep. 13, 327–335 (2015).

44

Lecka-Czernik, B. Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia 60, 1163–1169 (2017).

45

Son, H. S. et al. Benzydamine inhibits osteoclast differentiation and bone resorption via down-regulation of interleukin-1 beta expression. Acta Pharm. Sin. B 10, 462–474 (2020).

46

Aasarod, K. M. et al. Effects of the histamine 1 receptor antagonist cetirizine on the osteoporotic phenotype in H+/K(+)ATPase beta subunit KO mice. J. Cell. Biochem. 117, 2089–2096 (2016).

47

Yamaura, K., Yonekawa, T., Nakamura, T., Yano, S. & Ueno, K. The histamine H-2-receptor antagonist, cimetidine, inhibits the articular osteopenia in rats with adjuvant-induced arthritis by suppressing the osteoclast differentiation induced by histamine. J. Pharmacol. Sci. 92, 43–49 (2003).

48

Gomes, P. S., Resende, M. & Fernandes, M. H. Doxycycline restores the impaired osteogenic commitment of diabetic-derived bone marrow mesenchymal stromal cells by increasing the canonical WNT signaling. Mol. Cell Endocrinol. 518, 110975 (2020).

49
Drugbank online. Lidocaine, <https://go.drugbank.com/drugs/DB00281>(2021).
50

Li, L. et al. Polydopamine coating promotes early osteogenesis in 3D printing porous Ti6Al4V scaffolds. Ann. Transl. Med. 7, 14 (2019).

51

Hu, C. et al. Berberine/Ag nanoparticle embedded biomimetic calcium phosphate scaffolds for enhancing antibacterial function. Nanotechnol. Rev. 9, 568–579 (2020).

52

Sang, S., Wang, S. J., Yang, C., Geng, Z. & Zhang, X.L. Sponge-inspired sulfonated polyetheretherketone loaded with polydopamine-protected osthole nanoparticles and berberine enhances osteogenic activity and prevents implant-related infections. Chem. Eng. J. 437, 135255 (2022).

53

Chen, H., Yan, Y. F., Qi, J., Deng, L. F. & Cui, W. G. Sustained delivery of desferrioxamine via liposome carriers in hydrogel for combining angiogenesis and osteogenesis in bone defects reconstruction. J. Control. Release 259, E79–E79 (2017).

54

Song, W. et al. Doxycycline-loaded coaxial nanofiber coating of titanium implants enhances osseointegration and inhibits Staphylococcus aureus infection. Biomed. Mater. 12, 045008 (2017).

55

Wang, D., Zhang, P., Mei, X. & Chen, Z. Repair calvarial defect of osteoporotic rats by berberine functionalized porous calcium phosphate scaffold. Regen. Biomater. 8, 10 (2021).

56

Ozturk-Oncel, M. O., Odabas, S., Uzun, L., Hur, D. & Garipcan, B. A facile surface modification of poly(dimethylsiloxane) with amino acid conjugated self-assembled monolayers for enhanced osteoblast cell behavior. Colloids Surf. B Biointerfaces 196, 111343 (2020).

57

Cui, N., Han, K., Li, M., Wang, J. & Qian, J. Pure polylysine-based foamy scaffolds and their interaction with MC3T3-E1 cells and osteogenesis. Biomed. Mater. 15, 025004 (2020).

58

Ma, Y. et al. Three-dimensional printing of biodegradable piperazine-based polyurethane-urea scaffolds with enhanced osteogenesis for bone regeneration. ACS Appl. Mater. Interfaces 11, 9415–9424 (2019).

59

Mao, L. et al. Regulation of inflammatory response and osteogenesis to citrate-based biomaterials through incorporation of alkaline fragments. Adv. Health. Mater. 11, e2101590 (2022).

60

Pritchard, J. J. A cytological and histochemical study of bone and cartilage formation in the rat. J. Anat. 86, 259–277 (1952).

61

Young, M. F., Kerr, J. M., Ibaraki, K., Heegaard, A. M. & Robey, P. G. Structure, expression, and regulation of the major noncollagenous matrix proteins of bone. Clin. Orthop. Relat. Res. 281, 275–294 (1992).

62

Robey, P. G. et al. Structure and molecular regulation of bone matrix proteins. J. Bone Min. Res. 8, S483–S487 (1993).

63

Long, F. Building strong bones: molecular regulation of the osteoblast lineage. Nat. Rev. Mol. Cell Biol. 13, 27–38 (2011).

64

Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

65

Jaiswal, R. K. et al. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J. Biol. Chem. 275, 9645–9652 (2000).

66

Kim, J. M. et al. The ERK MAPK pathway is essential for skeletal development and homeostasis. Int. J. Mol. Sci. 20, 1803 (2019).

67

Wang, C. X. et al. Dopamine D1 receptor-mediated activation of the ERK signaling pathway is involved in the osteogenic differentiation of bone mesenchymal stem cells. Stem Cell Res. Ther. 11, 13 (2020).

68

Lee, H. W. et al. Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J. Bone Min. Res. 23, 1227–1237 (2008).

69

Xin, B. C. et al. Berberine promotes osteogenic differentiation of human dental pulp stem cells through activating EGFR-MAPK-Runx2 pathways. Pathol. Oncol. Res. 26, 1677–1685 (2020).

70

Kim, D. S. et al. Effects of glutamine on proliferation, migration, and differentiation of human dental pulp cells. J. Endod. 40, 1087–1094 (2014).

71

Yin, H. et al. Preventive effects of evodiamine on dexamethasone-induced osteoporosis in zebrafish. Biomed. Res. Int. 2019, 6 (2019).

72

Kim, H. K. et al. Salicylideneamino-2-thiophenol enhances osteogenic differentiation through the activation of MAPK pathways in multipotent bone marrow stem cell. J. Cell. Biochem. 113, 1833–1841 (2012).

73

Chan, Y. H. et al. Melatonin enhances osteogenic differentiation of dental pulp mesenchymal stem cells by regulating MAPK pathways and promotes the efficiency of bone regeneration in calvarial bone defects. Stem Cell Res. Ther. 13, 73 (2022).

74

Yuan, L. Q. et al. Taurine promotes connective tissue growth factor (CTGF) expression in osteoblasts through the ERK signal pathway. Amino Acids 32, 425–430 (2007).

75

Villa, I. et al. Betaine promotes cell differentiation of human osteoblasts in primary culture. J. Transl. Med. 15, 132 (2017).

76

Baron, R. & Kneissel, M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179–192 (2013).

77

Nusse, R. & Clevers, H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017).

78

Madan, B. et al. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res. 6, 17 (2018).

79

Zhang, L. N. et al. Berberine improves advanced glycation end products‑induced osteogenic differentiation responses in human periodontal ligament stem cells through the canonical Wnt/β‑catenin pathway. Mol. Med. Rep. 19, 5440–5452 (2019).

80

Yang, L. et al. Leonurine hydrochloride promotes osteogenic differentiation and increases osteoblastic bone formation in ovariectomized mice by Wnt/beta-catenin pathway. Biochem. Biophys. Res. Commun. 504, 941–948 (2018).

81

Li, C. et al. The protective effect of piperine on ovariectomy induced bone loss in female mice and its enhancement effect of osteogenic differentiation via Wnt/β-catenin signaling pathway. J. Funct. Food 58, 138–150 (2019).

82

Karner, C. M., Esen, E., Okunade, A. L., Patterson, B. W. & Long, F. Increased glutamine catabolism mediates bone anabolism in response to WNT signaling. J. Clin. Investig. 125, 551–562 (2015).

83

Seidlitz, E. P., Sharma, M. K. & Singh, G. Extracellular glutamate alters mature osteoclast and osteoblast functions. Can. J. Physiol. Pharm. 88, 929–936 (2010).

84

Schaffer, S. & Kim, H. W. Effects and mechanisms of taurine as a therapeutic agent. Biomol. Ther. 26, 225–241 (2018).

85

Prideaux, M., Kitase, Y., Kimble, M., O’Connell, T. M. & Bonewald, L. F. Taurine, an osteocyte metabolite, protects against oxidative stress-induced cell death and decreases inhibitors of the Wnt/beta-catenin signaling pathway. Bone 137, 115374 (2020).

86

Ma, Z. P., Liao, J. C., Zhao, C. & Cai, D. Z. Effects of the 1, 4-dihydropyridine L-type calcium channel blocker benidipine on bone marrow stromal cells. Cell Tissue Res. 361, 467–476 (2015).

87

Ma, J., Zhang, Z. L., Hu, X. T., Wang, X. T. & Chen, A. M. Metformin promotes differentiation of human bone marrow derived mesenchymal stem cells into osteoblast via GSK3beta inhibition. Eur. Rev. Med. Pharm. Sci. 22, 7962–7968 (2018).

88

Zhao, X. E. et al. 6-Bromoindirubin-3’-oxime promotes osteogenic differentiation of canine BMSCs through inhibition of GSK3beta activity and activation of the Wnt/beta-catenin signaling pathway. Acad. Bras. Cienc. 91, e20180459 (2019).

89

Fruman, D. A., Meyers, R. E. & Cantley, L. C. Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481–507 (1998).

90

Chen, J., Crawford, R., Chen, C. & Xiao, Y. The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng. Part B Rev. 19, 516–528 (2013).

91

Zhao, B. et al. Leonurine promotes the osteoblast differentiation of Rat BMSCs by activation of autophagy via the PI3K/Akt/mTOR pathway. Front. Bioeng. Biotechnol. 9, 615191 (2021).

92

Mirones, I. et al. Dopamine mobilizes mesenchymal progenitor cells through D2-class receptors and their PI3K/AKT pathway. Stem Cells 32, 2529–2538 (2014).

93

Ma, P. et al. Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism 59, 359–366 (2010).

94

Evans, B. A. J. et al. Human osteoblast precursors produce extracellular adenosine, which modulates their secretion of IL-6 and osteoprotegerin. J. Bone Miner. Res. 21, 228–236 (2006).

95

Gharibi, B., Abraham, A. A., Ham, J. & Evans, B. A. J. Adenosine receptor subtype expression and activation influence the differentiation of mesenchymal stem cells to osteoblasts and adipocytes. J. Bone Miner. Res. 26, 2112–2124 (2011).

96

Carroll, S. H. et al. A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo. J. Biol. Chem. 287, 15718–15727 (2012).

97

Borhani, S., Corciulo, C., Larranaga-Vera, A. & Cronstein, B. N. Adenosine A(2A) receptor (A2AR) activation triggers Akt signaling and enhances nuclear localization of beta-catenin in osteoblasts. FASEB J. 33, 7555–7562 (2019).

98

Ryu, J. et al. Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J. 25, 5840–5851 (2006).

99

Grey, A. et al. The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. Endocrinology 143, 4755–4763 (2002).

100

Matsuzaki, E. et al. Sphingosine-1-phosphate promotes the nuclear translocation of beta-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines. Bone 55, 315–324 (2013).

101

Endo, H., Nito, C., Kamada, H., Nishi, T. & Chan, P. H. Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J. Cereb. Blood Flow. Metab. 26, 1479–1489 (2006).

102

Pantovic, A. et al. Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. Bone 52, 524–531 (2013).

103

Chava, S., Chennakesavulu, S., Gayatri, B. M. & Reddy, A. B. M. A novel phosphorylation by AMP-activated kinase regulates RUNX2 from ubiquitination in osteogenesis over adipogenesis. Cell Death Dis. 9, 754 (2018).

104

Adil, M., Mansoori, M. N., Singh, D., Kandhare, A. D. & Sharma, M. Pioglitazone-induced bone loss in diabetic rats and its amelioration by berberine: a portrait of molecular crosstalk. Biomed. Pharmacother. 94, 1010–1019 (2017).

105

Kim, D. Y., Kim, E. J. & Jang, W. G. Piperine induces osteoblast differentiation through AMPK-dependent Runx2 expression. Biochem. Biophys. Res. Commun. 495, 1497–1502 (2018).

106

Zhang, F. Z., Xie, J. L., Wang, G. L., Zhang, G. & Yang, H. L. Anti-osteoporosis activity of Sanguinarine in preosteoblast MC3T3-E1 cells and an ovariectomized rat model. J. Cell. Physiol. 233, 4626–4633 (2018).

107

Zhao, X. et al. Metformin enhances osteogenic differentiation of stem cells from human-exfoliated deciduous teeth through AMPK pathway. J. Tissue Eng. Regen. Med. 14, 1869–1879 (2020).

108

Xu, D. et al. OSU53 rescues human OB-6 osteoblastic cells from dexamethasone through activating AMPK signaling. PLoS One 11, e0162694 (2016).

109

Kim, J. E. et al. AMPK activator, AICAR, inhibits palmitate-induced apoptosis in osteoblast. Bone 43, 394–404 (2008).

110

Zhu, Y., Zhou, J., Ao, R. & Yu, B. A-769662 protects osteoblasts from hydrogen dioxide-induced apoptosis through activating of AMP-activated protein kinase (AMPK). Int. J. Mol. Sci. 15, 11190–11203 (2014).

111

Liu, W. et al. Targeted activation of AMPK by GSK621 ameliorates H2O2-induced damages in osteoblasts. Oncotarget 8, 10543–10552 (2017).

112

Wu, Y. H., Li, Q., Li, P. & Liu, B. GSK621 activates AMPK signaling to inhibit LPS-induced TNFalpha production. Biochem. Biophys. Res. Commun. 480, 289–295 (2016).

113

Rankin, E. B. et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 149, 63–74 (2012).

114

Stegen, S. et al. HIF-1 alpha promotes glutamine-mediated redox homeostasis and glycogen-dependent bioenergetics to support postimplantation bone cell survival. Cell Metab. 23, 265–279 (2016).

115

Jing, X. Z. et al. Desferoxamine protects against glucocorticoid-induced osteonecrosis of the femoral head via activating HIF-1 alpha expression. J. Cell. Physiol. 235, 9864–9875 (2020).

116

Chen, J. & Long, F. mTOR signaling in skeletal development and disease. Bone Res. 6, 1 (2018).

117

Lv, C. et al. Glucosamine promotes osteoblast proliferation by modulating autophagy via the mammalian target of rapamycin pathway. Biomed. Pharmacother. 99, 271–277 (2018).

118

Ma, Y. H. et al. Glucosamine promotes chondrocyte proliferation via the Wnt/beta-catenin signaling pathway. Int. J. Mol. Med. 42, 61–70 (2018).

119

Sun, J. et al. Histone demethylase LSD1 regulates bone mass by controlling WNT7B and BMP2 signaling in osteoblasts. Bone Res. 6, 14 (2018).

120

Yonezawa, T. et al. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling. Biochem. Biophys. Res. Commun. 409, 260–265 (2011).

121

Liang, C., Sun, R. X., Xu, Y. F., Geng, W. & Li, J. Effect of the abnormal expression of BMP-4 in the blood of diabetic patients on the osteogenic differentiation potential of alveolar BMSCs and the rescue effect of metformin: a bioinformatics-based study. Biomed. Res. Int. 2020, 19 (2020).

122

Li, H. W. et al. γ-Aminobutyric acid promotes osteogenic differentiation of mesenchymal stem cells by inducing TNFAIP3. Curr. Gene Ther. 20, 152–161 (2020).

123

Wu, X., Walker, J., Zhang, J., Ding, S. & Schultz, P. G. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. Chem. Biol. 11, 1229–1238 (2004).

124

Zhou, T., Yang, Y. Q., Chen, Q. M. & Xie, L. Glutamine metabolism is essential for stemness of bone marrow mesenchymal stem cells and bone homeostasis. Stem Cells Int. 2019, 13 (2019).

125

Yu, Y. L. et al. Glutamine metabolism regulates proliferation and lineage allocation in skeletal stem cells. Cell Metab. 29, 966–978 (2019).

126

Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).

127

Marzia, M. et al. Decreased c-Src expression enhances osteoblast differentiation and bone formation. J. Cell Biol. 151, 311–320 (2000).

128

Peruzzi, B. et al. c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling. Nat. Commun. 3, 630 (2012).

129

Garcia-Gomez, A. et al. Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects. PLoS One 7, e34914 (2012).

130

Nie, P. et al. Dasatinib promotes chondrogenic differentiation of human mesenchymal stem cells via the Src/Hippo-YAP signaling pathway. ACS Biomater. Sci. Eng. 5, 5255–5265 (2019).

131

Wang, L. et al. Antiosteoporotic effects of tetramethylpyrazine via promoting osteogenic differentiation and inhibiting osteoclast formation. Mol. Med. Rep. 16, 8307–8314 (2017).

132

Liu, F. L., Chen, C. L., Lai, C. C., Lee, C. C. & Chang, D. M. Arecoline suppresses RANKL-induced osteoclast differentiation in vitro and attenuates LPS-induced bone loss in vivo. Phytomedicine 69, 11 (2020).

133

Jo, Y. J. et al. Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis. J. Cell Physiol. 236, 1854–1865 (2021).

134

Takayanagi, H. RANKL as the master regulator of osteoclast differentiation. J. Bone Min. Metab. 39, 13–18 (2021).

135

Matsumoto, M., Sudo, T., Saito, T., Osada, H. & Tsujimoto, M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J. Biol. Chem. 275, 31155–31161 (2000).

136

Li, H. W. et al. Sanguinarine inhibits osteoclast formation and bone resorption via suppressing RANKL-induced activation of NF-kappa B and ERK signaling pathways. Biochem. Biophys. Res. Commun. 430, 951–956 (2013).

137

Deepak, V., Kruger, M. C., Joubert, A. & Coetzee, M. Piperine alleviates osteoclast formation through the p38/c-Fos/NFATc1 signaling axis. Biofactors 41, 403–413 (2015).

138

Zhang, J. et al. Deferoxamine inhibits iron-uptake stimulated osteoclast differentiation by suppressing electron transport chain and MAPKs signaling. Toxicol. Lett. 313, 50–59 (2019).

139

Wei, Z. F. et al. Norisoboldine suppresses osteoclast differentiation through preventing the accumulation of TRAF6-TAK1 complexes and activation of MAPKs/NF-kappa B/c-Fos/NFATc1 pathways. PLoS One 8, 16 (2013).

140

Qian, Z. et al. Cytisine attenuates bone loss of ovariectomy mouse by preventing RANKL-induced osteoclastogenesis. J. Cell Mol. Med. 24, 10112–10127 (2020).

141

Zhi, X. et al. l-tetrahydropalmatine suppresses osteoclastogenesis in vivo and in vitro via blocking RANK-TRAF6 interactions and inhibiting NF-kappa B and MAPK pathways. J. Cell. Mol. Med. 24, 785–798 (2020).

142

Matsushita, T. et al. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol. Cell Biol. 29, 5843–5857 (2009).

143

Karin, M. Nuclear factor-kappaB in cancer development and progression. Nature 441, 431–436 (2006).

144

Franzoso, G. et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev. 11, 3482–3496 (1997).

145

Dougall, W. C. et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412–2424 (1999).

146

Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

147

Kong, Y. Y., Boyle, W. J. & Penninger, J. M. Osteoprotegerin ligand: a common link between osteoclastogenesis, lymph node formation and lymphocyte development. Immunol. Cell Biol. 77, 188–193 (1999).

148

Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).

149

Chen, X., Zhi, X., Wang, J. & Su, J. RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation. Bone Res. 6, 34 (2018).

150

Yamashita, T. et al. NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J. Biol. Chem. 282, 18245–18253 (2007).

151

Song, C. et al. Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation. FASEB J. 34, 4798–4811 (2020).

152

Kang, E. J. et al. Liensinine and nuciferine, bioactive components of nelumbo nucifera, inhibit the growth of breast cancer cells and breast cancer-associated bone loss. Evid. Based Complement. Altern. Med. 2017, 1583185 (2017).

153

Chen, S. et al. Neferine suppresses osteoclast differentiation through suppressing NF-kappaB signal pathway but not MAPKs and promote osteogenesis. J. Cell Physiol. 234, 22960–22971 (2019).

154

Hu, B. et al. Tomatidine suppresses osteoclastogenesis and mitigates estrogen deficiency-induced bone mass loss by modulating TRAF6-mediated signaling. Faseb J. 33, 2574–2586 (2019).

155

Yun, J., Lee, K. Y. & Park, B. Neotuberostemonine inhibits osteoclastogenesis via blockade of NF-kappa B pathway. Biochimie 157, 81–91 (2019).

156

Takahashi, T. et al. Tetrandrine prevents bone loss in sciatic-neurectomized mice and inhibits receptor activator of nuclear factor kappa B ligand-induced osteoclast differentiation. Biol. Pharm. Bull. 35, 1765–1774 (2012).

157

Liu, Z. et al. Tetrandrine inhibits titanium particle-induced inflammatory osteolysis through the nuclear factor-kappaB pathway. Mediat. Inflamm. 2020, 1926947 (2020).

158

Zhong, Z. Y. et al. Tetrandrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis. Front. Pharmacol. 10, 14 (2020).

159

Wei, Z. F. et al. Norisoboldine, an anti-arthritis alkaloid isolated from radix linderae, attenuates osteoclast differentiation and inflammatory bone erosion in an aryl hydrocarbon receptor-dependent manner. Int. J. Biol. Sci. 11, 1113–1126 (2015).

160

Guo, J. et al. Meclizine prevents ovariectomy-induced bone loss and inhibits osteoclastogenesis partially by upregulating PXR. Front. Pharm. 8, 693 (2017).

161

Yamamoto, T. et al. The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. Br. J. Pharm. 166, 1084–1096 (2012).

162

Zhao, H. et al. Berberine ameliorates cartilage degeneration in interleukin-1beta-stimulated rat chondrocytes and in a rat model of osteoarthritis via Akt signalling. J. Cell Mol. Med. 18, 283–292 (2014).

163

Moon, J. B. et al. Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J. Immunol. 188, 163–169 (2012).

164

Meng, J. H. et al. Stachydrine prevents LPS-induced bone loss by inhibiting osteoclastogenesis via NF-kappa B and Akt signalling. J. Cell. Mol. Med. 23, 6730–6743 (2019).

165

Li, S. T. et al. SC79 rescues osteoblasts from dexamethasone though activating Akt-Nrf2 signaling. Biochem. Biophys. Res. Commun. 479, 54–60 (2016).

166

Zhu, R., Chen, Y. X., Ke, Q. F., Gao, Y. S. & Guo, Y. P. SC79-loaded ZSM-5/chitosan porous scaffolds with enhanced stem cell osteogenic differentiation and bone regeneration. J. Mater. Chem. B 5, 5009–5018 (2017).

167

Hua, P. et al. Diaporisoindole E inhibits RANKL-induced osteoclastogenesis via suppression of PI3K/AKT and MAPK signal pathways. Phytomedicine 75, 8 (2020).

168

Holliday, L. S. Vacuolar H(+)-ATPases (V-ATPases) as therapeutic targets: a brief review and recent developments. Biotarget 1, 1–14 (2017).

169

Blair, H. C., Teitelbaum, S. L., Ghiselli, R. & Gluck, S. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 245, 855–857 (1989).

170

Kartner, N. & Manolson, M. F. Novel techniques in the development of osteoporosis drug therapy: the osteoclast ruffled-border vacuolar H(+)-ATPase as an emerging target. Expert Opin. Drug Discov. 9, 505–522 (2014).

171

Visentin, L. et al. A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J. Clin. Investig. 106, 309–318 (2000).

172

Duan, X., Yang, S., Zhang, L. & Yang, T. V-ATPases and osteoclasts: ambiguous future of V-ATPases inhibitors in osteoporosis. Theranostics 8, 5379–5399 (2018).

173

Kartner, N. et al. Inhibition of osteoclast bone resorption by disrupting vacuolar H+-ATPase a3-B2 subunit interaction. J. Biol. Chem. 285, 37476–37490 (2010).

174

Toro, E. J. et al. Enoxacin directly inhibits osteoclastogenesis without inducing apoptosis. J. Biol. Chem. 287, 17894–17904 (2012).

175

Yamaguchi, N. et al. Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling. FEBS Lett. 582, 451–456 (2008).

176

Uemura, T. et al. Epinephrine accelerates osteoblastic differentiation by enhancing bone morphogenetic protein signaling through a cAMP/protein kinase A signaling pathway. Bone 47, 756–765 (2010).

177

Claes, L., Recknagel, S. & Ignatius, A. Fracture healing under healthy and inflammatory conditions. Nat. Rev. Rheumatol. 8, 133–143 (2012).

178

Jimi, E. et al. Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells. Exp. Cell Res. 247, 84–93 (1999).

179

Azuma, Y., Kaji, K., Katogi, R., Takeshita, S. & Kudo, A. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J. Biol. Chem. 275, 4858–4864 (2000).

180

Liu, X. H., Kirschenbaum, A., Yao, S. & Levine, A. C. Cross-talk between the interleukin-6 and prostaglandin E(2) signaling systems results in enhancement of osteoclastogenesis through effects on the osteoprotegerin/receptor activator of nuclear factor-{kappa}B (RANK) ligand/RANK system. Endocrinology 146, 1991–1998 (2005).

181

Marcu, K. B., Otero, M., Olivotto, E., Borzi, R. M. & Goldring, M. B. NF-kappaB signaling: multiple angles to target OA. Curr. drug targets 11, 599–613 (2010).

182

Lin, T. H. et al. NF-kappaB as a therapeutic target in inflammatory-associated bone diseases. Adv. Protein Chem. Struct. Biol. 107, 117–154 (2017).

183

Wojdasiewicz, P., Poniatowski, L. A. & Szukiewicz, D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat. Inflamm. 2014, 561459 (2014).

184

Chen, Z. et al. Spermidine activates RIP1 deubiquitination to inhibit TNF-alpha-induced NF-kappaB/p65 signaling pathway in osteoarthritis. Cell Death Dis. 11, 503 (2020).

185

Gao, B. et al. Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti-inflammatory and angiogenic environment in aging mice. Aging Cell 17, e12741 (2018).

186

Yu, T., Qu, J., Wang, Y. & Jin, H. Ligustrazine protects chondrocyte against IL-1beta induced injury by regulation of SOX9/NF-kappaB signaling pathway. J. Cell Biochem. 119, 7419–7430 (2018).

187

Duan, Y., An, W., Wu, Y. & Wang, J. Tetramethylpyrazine reduces inflammation levels and the apoptosis of LPSstimulated human periodontal ligament cells via the downregulation of miR302b. Int. J. Mol. Med. 45, 1918–1926 (2020).

188

Wong, S. K., Chin, K. Y. & Ima-Nirwana, S. Berberine and musculoskeletal disorders: the therapeutic potential and underlying molecular mechanisms. Phytomedicine 73, 152892 (2020).

189

Park, H. J., Zadeh, M. G., Suh, J. H. & Choi, H. S. Dauricine protects from LPS-induced bone loss via the ROS/PP2A/NF-kappa B Axis in osteoclasts. Antioxidants 9, 15 (2020).

190

Tajima, Y. et al. Nitensidine A, a guanidine alkaloid from Pterogyne nitens, induces osteoclastic cell death. Cytotechnology 67, 585–592 (2015).

191
192
193

Yoshikawa, R. & Abe, K. The multi-kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis. Cell Biochem. Funct. 39, 521–527 (2021).

194

Klabunde, R. E. Dipyridamole inhibition of adenosine metabolism in human blood. Eur. J. Pharm. 93, 21–26 (1983).

195

Ohashi, E. et al. Adenosine N1-oxide exerts anti-inflammatory effects through the PI3K/Akt/GSK-3beta signaling pathway and promotes osteogenic and adipocyte differentiation. Biol. Pharm. Bull. 42, 968–976 (2019).

196

Domazetovic, V., Marcucci, G., Iantomasi, T., Brandi, M. L. & Vincenzini, M. T. Oxidative stress in bone remodeling: role of antioxidants. Clin. Cases Min. Bone Metab. 14, 209–216 (2017).

197

Chung, H. Y. et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev. 8, 18–30 (2009).

198
Duarte, T. L., Talbot, N. P. & Drakesmith, H. NRF2 and hypoxia-inducible factors: key players in the redox control of systemic iron homeostasis. Antioxid. Redox Signal. 35, 433–452 (2021).
199

Thompson, C. B. Into Thin air: how we sense and respond to hypoxia. Cell 167, 9–11 (2016).

200

Ishii, T. et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem. 275, 16023–16029 (2000).

201

Motohashi, H. & Yamamoto, M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol. Med. 10, 549–557 (2004).

202

Cho, H. Y., Reddy, S. P. & Kleeberger, S. R. Nrf2 defends the lung from oxidative stress. Antioxid. Redox Signal. 8, 76–87 (2006).

203

Yamamoto, M., Kensler, T. W. & Motohashi, H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol. Rev. 98, 1169–1203 (2018).

204

Hyeon, S., Lee, H., Yang, Y. & Jeong, W. Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radic. Biol. Med. 65, 789–799 (2013).

205

Chen, X. et al. Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis. Bone Res. 9, 15 (2021).

206

Jia, L. L., Xiong, Y. X., Zhang, W. J., Ma, X. N. & Xu, X. Metformin promotes osteogenic differentiation and protects against oxidative stress-induced damage in periodontal ligament stem cells via activation of the Akt/Nrf2 signaling pathway. Exp. Cell Res. 386, 12 (2020).

207

Guo, S. et al. Activating AMP-activated protein kinase by an alpha1 selective activator compound 13 attenuates dexamethasone-induced osteoblast cell death. Biochem. Biophys. Res. Commun. 471, 545–552 (2016).

208

Joo, M. S. et al. AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Mol. Cell. Biol. 36, 1931–1942 (2016).

209

Zhan, Y. F. et al. Vindoline inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss in mice. Front. Pharmacol. 10, 11 (2020).

210

Wu, X. et al. Pyrroloquinoline quinone prevents testosterone deficiency-induced osteoporosis by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. Am. J. Transl. Res. 9, 1230–1242 (2017).

211

Barzel, U. S. & Jowsey, J. The effects of chronic acid and alkali administration on bone turnover in adult rats. Clin. Sci. 36, 517–524 (1969).

212

Arnett, T. R. & Dempster, D. W. Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology 119, 119–124 (1986).

213

Brandao-Burch, A., Utting, J. C., Orriss, I. R. & Arnett, T. R. Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization. Calcif. Tissue Int. 77, 167–174 (2005).

214

Blair, H. C. et al. Support of bone mineral deposition by regulation of pH. Am. J. Physiol. Cell Physiol. 315, C587–c597 (2018).

215

Bushinsky, D. A. Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Am. J. Physiol. 271, F216–F222 (1996).

216

Kohn, D. H., Sarmadi, M., Helman, J. I. & Krebsbach, P. H. Effects of pH on human bone marrow stromal cells in vitro: implications for tissue engineering of bone. J. Biomed. Mater. Res. 60, 292–299 (2002).

217

Galow, A. M. et al. Increased osteoblast viability at alkaline pH in vitro provides a new perspective on bone regeneration. Biochem. Biophys. Rep. 10, 17–25 (2017).

218

Han, S. H. et al. Acidic pH environments increase the expression of cathepsin B in osteoblasts: the significance of ER stress in bone physiology. Immunopharmacol. Immunotoxicol. 31, 428–431 (2009).

219

Spector, J. A. et al. Osteoblast expression of vascular endothelial growth factor is modulated by the extracellular microenvironment. Am. J. Physiol. Cell Physiol. 280, C72–C80 (2001).

220

Liu, W. et al. Akermanite used as an alkaline biodegradable implants for the treatment of osteoporotic bone defect. Bioact. Mater. 1, 151–159 (2016).

221

Liu, W. et al. Spatial distribution of biomaterial microenvironment ph and its modulatory effect on osteoclasts at the early stage of bone defect regeneration. ACS Appl. Mater. Interfaces 11, 9557–9572 (2019).

222

Ruan, C. et al. The interfacial pH of acidic degradable polymeric biomaterials and its effects on osteoblast behavior. Sci. Rep. 7, 6794 (2017).

223

Sabe, V. T. et al. Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: a review. Eur. J. Med. Chem. 5, 113705 (2021).

224

Liao, L. X. et al. Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation therapy. Proc. Natl. Acad. Sci. USA 114, E5986–E5994 (2017).

225

Lee, J. S., Yi, J. K., An, S. Y. & Heo, J. S. Increased osteogenic differentiation of periodontal ligament stem cells on polydopamine film occurs via activation of integrin and PI3K signaling pathways. Cell. Physiol. Biochem. 34, 1824–1834 (2014).

226

Hanami, K. et al. Dopamine D2-like receptor signaling suppresses human osteoclastogenesis. Bone 56, 1–8 (2013).

227

Lee, D. J. et al. Dopaminergic effects on in vitro osteogenesis. Bone Res. 3, 15020 (2015).

228

Cao, L. et al. Melatonin mediates osteoblast proliferation through the STIM1/ORAI1 pathway. Front. Pharm. 13, 851663 (2022).

229

Wang, X. et al. Melatonin promotes bone marrow mesenchymal stem cell osteogenic differentiation and prevents osteoporosis development through modulating circ_0003865 that sponges miR-3653-3p. Stem Cell Res. Ther. 12, 150 (2021).

230

Han, Y., Kim, Y. M., Kim, H. S. & Lee, K. Y. Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression. Sci. Rep. 7, 5716 (2017).

231

Kim, S.-S., Jeong, S.-P., Park, B.-S. & Kim, I.-R. Melatonin attenuates RANKL-induced osteoclastogenesis via inhibition of Atp6v0d2 and DC-STAMP through MAPK and NFATc1 signaling pathways. Molecules 27, 1–13 (2022).

232

Xu, L. et al. Melatonin suppresses estrogen deficiency-induced osteoporosis and promotes osteoblastogenesis by inactivating the NLRP3 inflammasome. Calcif. Tissue Int. 103, 400–410 (2018).

233

Lee, S., Le, N. H. & Kang, D. Melatonin alleviates oxidative stress-inhibited osteogenesis of human bone marrow-derived mesenchymal stem cells through AMPK activation. Int. J. Med. Sci. 15, 1083–1091 (2018).

234

Du, Z. H. et al. Adenosine A2A receptor mediates inhibition of synovitis and osteoclastogenesis after electroacupuncture in rats with collagen-induced arthritis. Evid.-Based Complement. Altern. Med. 2019, 11 (2019).

235

Kim, B. H., Oh, J. H. & Lee, N. K. The inactivation of ERK1/2, p38 and NF-kappa B is involved in the down-regulation of osteoclastogenesis and function by A2B adenosine receptor stimulation. Mol. Cells 40, 752–760 (2017).

236

Borhani, S., Corciulo, C., Larranaga-Vera, A. & Cronstein, B. N. Signaling at adenosine A2A receptors (A2aR); crosstalk with Wnt/beta-catenin signaling pathway in osteoblasts. Purinergic Signal. 14, S55–S55 (2018).

237

Olkku, A. & Mahonen, A. Wnt and steroid pathways control glutamate signalling by regulating glutamine synthetase activity in osteoblastic cells. Bone 43, 483–493 (2008).

238

Yuan, L. Q. et al. Taurine transporter is expressed in osteoblasts. Amino Acids 31, 157–163 (2006).

239

Yuan, L. Q. et al. Taurine inhibits osteoclastogenesis through the taurine transporter. Amino Acids 39, 89–99 (2010).

240
Kang, I. S. & Kim, C. Taurine 11 Advances in Experimental Medicine and Biology (eds J. Hu et al.) Vol. 1155 p,p. 61–70 (Springer International Publishing Ag, 2019).
241

Facchini, A. et al. Role of polyamines in hypertrophy and terminal differentiation of osteoarthritic chondrocytes. Amino Acids 42, 667–678 (2012).

242

D’Adamo, S. et al. Spermidine rescues the deregulated autophagic response to oxidative stress of osteoarthritic chondrocytes. Free Radic. Biol. Med. 153, 159–172 (2020).

243

Guidotti, S. et al. Enhanced osteoblastogenesis of adipose-derived stem cells on spermine delivery via beta-catenin activation. Stem Cells Dev. 22, 1588–1601 (2013).

244

Mandl, P. et al. Nicotinic acetylcholine receptor ligands inhibit osteoclastogenesis by blocking Rankl-induced calcium-oscillation and induction of Nfatc1 and Cfos. Ann. Rheum. Dis. 73, A58–A59 (2014).

245

Yang, Q. et al. Betaine alleviates alcohol-induced osteonecrosis of the femoral head via mTOR signaling pathway regulation. Biomed. Pharmacother. 120, 109486 (2019).

246

Santos, C. et al. Development of hydroxyapatite nanoparticles loaded with folic acid to induce osteoblastic differentiation. Int. J. Pharm. 516, 185–195 (2017).

247

Akpinar, A. et al. Comparative effects of riboflavin, nicotinamide and folic acid on alveolar bone loss: a morphometric and histopathologic study in rats. Srp. Arh. Celok. Lek. 144, 273–279 (2016).

248

Wu, X., Zhou, X., Liang, S., Zhu, X. & Dong, Z. The mechanism of pyrroloquinoline quinone influencing the fracture healing process of estrogen-deficient mice by inhibiting oxidative stress. Biomed. Pharmacother. 139, 111598 (2021).

249

Hashimoto, Y. et al. Sphingosine-1-phosphate-enhanced Wnt5a promotes osteogenic differentiation in C3H10T1/2 cells. Cell Biol. Int. 40, 1129–1136 (2016).

250

Ran, Q. C. et al. Deferoxamine loaded titania nanotubes substrates regulate osteogenic and angiogenic differentiation of MSCs via activation of HIF-1 alpha signaling. Mat. Sci. Eng. C-Mater. 91, 44–54 (2018).

251

Shi, R. et al. Electrospun artificial periosteum loaded with DFO contributes to osteogenesis via the TGF-beta1/Smad2 pathway. Biomater. Sci. 9, 2090–2102 (2021).

252

Fan, K.-J. et al. Metformin inhibits inflammation and bone destruction in collagen-induced arthritis in rats. Ann. Transl. Med. 8, 1565 (2020).

253

Gao, X. L. et al. Effects oF Targeted Delivery Of Metformin And Dental Pulp Stem Cells On Osteogenesis Via Demineralized Dentin Matrix Under High Glucose Conditions. ACS Biomater. Sci. Eng. 6, 2346–2356 (2020).

254

Lin, J. T., Xu, R. Y., Shen, X., Jiang, H. B. & Du, S. H. Metformin promotes the osseointegration of titanium implants under osteoporotic conditions by regulating BMSCs autophagy, and osteogenic differentiation. Biochem. Biophys. Res. Commun. 531, 228–235 (2020).

255

Gu, Q., Gu, Y., Yang, H. & Shi, Q. Metformin Enhances Osteogenesis And Suppresses Adipogenesis Of Human Chorionic Villous Mesenchymal Stem Cells. Tohoku J. Exp. Med. 241, 13–19 (2017).

256

Marycz, K. et al. Metformin decreases reactive oxygen species, enhances osteogenic properties of adipose-derived multipotent mesenchymal stem cells in vitro, and increases bone density in vivo. Oxid. Med. Cell Longev. 2016, 9785890 (2016).

257

Bahrambeigi, S., Yousefi, B., Rahimi, M. & Shafiei-Irannejad, V. Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomed. Pharmacother. 109, 1593–1601 (2019).

258

Liu, Z. et al. The effects of tranylcypromine on osteoclastogenesis in vitro and in vivo. FASEB J. 33, 9828–9841 (2019).

259

LaBranche, T. P. et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 64, 3531–3542 (2012).

260

Yannaki, E. et al. The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats. Arthritis Rheum. 62, 3277–3288 (2010).

261

Pennypacker, B. L. et al. Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model. J. Orthop. Res. 34, 72–80 (2016).

262

Khosla, S. Odanacatib: location and timing are everything. J. Bone Min. Res. 27, 506–508 (2012).

263

Hao, L. et al. A small molecule, odanacatib, inhibits inflammation and bone loss caused by endodontic disease. Infect. Immun. 83, 1235–1245 (2015).

264

Wang, Y., Fu, Q. & Zhao, W. Tetramethylpyrazine inhibits osteosarcoma cell proliferation via downregulation of NF-kappaB in vitro and in vivo. Mol. Med. Rep. 8, 984–988 (2013).

265

Jia, X. et al. Berberine ameliorates periodontal bone loss by regulating gut microbiota. J. Dent. Res. 98, 107–116 (2019).

266

Liu, M. & Xu, Z. Berberine promotes the proliferation and osteogenic differentiation of alveolar osteoblasts through regulating the expression of miR-214. Pharmacology 106, 70–78 (2021).

267

Fukuma, Y. et al. Rutaecarpine attenuates osteoclastogenesis by impairing macrophage colony stimulating factor and receptor activator of nuclear factor -B ligand-stimulated signalling pathways. Clin. Exp. Pharmacol. Physiol. 45, 863–865 (2018).

268

Chen, S. et al. Lycorine suppresses RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced osteoporosis and titanium particle-induced osteolysis in vivo. Sci. Rep. 5, 13 (2015).

269

Park, H. J., Gholam-Zadeh, M., Suh, J. H. & Choi, H. S. Lycorine attenuates autophagy in osteoclasts via an axis of mROS/TRPML1/TFEB to Reduce LPS-induced bone loss. Oxid. Med. Cell. Longev. 2019, 11 (2019).

270

He, L. G. et al. Sinomenine induces apoptosis in RAW 264.7 cell-derived osteoclasts in vitro via caspase-3 activation. Acta Pharmacol. Sin. 35, 203–210 (2014).

271

He, L. G. et al. Sinomenine down-regulates TLR4/TRAF6 expression and attenuates lipopolysaccharide-induced osteoclastogenesis and osteolysis. Eur. J. Pharmacol. 779, 66–79 (2016).

272

Zhang, Y. Y. et al. Sinomenine inhibits osteolysis in breast cancer by reducing IL-8/CXCR1 and c-Fos/NFATc1 signaling. Pharmacol. Res. 142, 140–150 (2019).

273

Zheng, T., Noh, A., Park, H. & Yim, M. Aminocoumarins inhibit osteoclast differentiation and bone resorption via downregulation of nuclear factor of activated T cells c1. Biochem. Pharmacol. 85, 417–425 (2013).

274

Clough, B. H. et al. Theobromine upregulates osteogenesis by human mesenchymal stem cells in vitro and accelerates bone development in rats. Calcif. Tissue Int. 100, 298–310 (2017).

275

Yuan, F. L. et al. Leonurine hydrochloride inhibits osteoclastogenesis and prevents osteoporosis associated with estrogen deficiency by inhibiting the NF-kappaB and PI3K/Akt signaling pathways. Bone 75, 128–137 (2015).

276

Yonezawa, T. et al. Harmine, a beta-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo. Eur. J. Pharmacol. 650, 511–518 (2011).

277

Chen, X. et al. Matrine derivate MASM uncovers a novel function for ribosomal protein S5 in osteoclastogenesis and postmenopausal osteoporosis. Cell Death Dis. 8, e3037 (2017).

278

Xin, Z. et al. A matrine derivative M54 suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by targeting ribosomal protein S5. Front. Pharm. 9, 22 (2018).

279

Li, J. et al. Matrine enhances osteogenic differentiation of bone marrow-derived mesenchymal stem cells and promotes bone regeneration in rapid maxillary expansion. Arch. Oral. Biol. 118, 104862 (2020).

280

Kwak, S. C. et al. Securinine suppresses osteoclastogenesis and ameliorates inflammatory bone loss. Phytother. Res. 34, 3029–3040 (2020).

281

Sun, Z. et al. Magnoflorine suppresses MAPK and NF-kappaB signaling to prevent inflammatory osteolysis induced by titanium particles in vivo and osteoclastogenesis via RANKL in vitro. Front. Pharm. 11, 389 (2020).

282

Liu, Q. et al. Nitidine chloride prevents OVX-induced bone loss via suppressing NFATc1-mediated osteoclast differentiation. Sci. Rep. 6, 36662 (2016).

283

Bowers, A. et al. Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor. J. Am. Chem. Soc. 130, 11219–11222 (2008).

284

Lee, S. U. et al. In vitro and in vivo osteogenic activity of largazole. ACS Med. Chem. Lett. 2, 248–251 (2011).

285

Farina, C. & Gagliardi, S. Selective inhibition of osteoclast vacuolar H(+)-ATPase. Curr. Pharm. Des. 8, 2033–2048 (2002).

286

Niikura, K., Takeshita, N. & Takano, M. A vacuolar ATPase inhibitor, FR167356, prevents bone resorption in ovariectomized rats with high potency and specificity: potential for clinical application. J. Bone Min. Res. 20, 1579–1588 (2005).

287

Niikura, K., Takeshita, N. & Chida, N. A novel inhibitor of vacuolar ATPase, FR202126, prevents alveolar bone destruction in experimental periodontitis in rats. J. Toxicol. Sci. 30, 297–304 (2005).

288

Niikura, K. Comparative analysis of the effects of a novel vacuolar adenosine 5’-triphosphatase inhibitor, FR202126, and doxycycline on bone loss caused by experimental periodontitis in rats. J. Periodontol. 77, 1211–1216 (2006).

289

Niikura, K., Nakajima, S., Takano, M. & Yamazaki, H. FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats. Bone 40, 888–894 (2007).

290

Liou, S. F. et al. KMUP-1 promotes osteoblast differentiation through cAMP and cGMP pathways and signaling of BMP-2/Smad1/5/8 and Wnt/beta-catenin. J. Cell Physiol. 230, 2038–2048 (2015).

291

Yuan, Y. et al. Fumitremorgin C attenuates osteoclast formation and function via suppressing RANKL-induced signaling pathways. Front. Pharm. 11, 238 (2020).

Bone Research
Article number: 40
Cite this article:
Zhang Q, Yang J, Hu N, et al. Small-molecule amines: a big role in the regulation of bone homeostasis. Bone Research, 2023, 11: 40. https://doi.org/10.1038/s41413-023-00262-z

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Received: 15 July 2022
Revised: 14 March 2023
Accepted: 31 March 2023
Published: 24 July 2023
© The Author(s) 2023

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