Advertisement

Current Osteoporosis Reports

, Volume 17, Issue 4, pp 169–177 | Cite as

CaMKK2 Signaling in Metabolism and Skeletal Disease: a New Axis with Therapeutic Potential

  • Justin N. Williams
  • Uma SankarEmail author
Skeletal Biology and Regulation (M Forwood and A Robling, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Skeletal Biology and Regulation

Abstract

Purpose of Review

Age and metabolic disorders result in the accumulation of advanced glycation endproducts (AGEs), oxidative stress, and inflammation, which cumulatively cause a decline in skeletal health. Bone becomes increasingly vulnerable to fractures and its regenerative capacity diminishes under such conditions. With a rapidly aging population in the USA and the global increase in diabetes, efficacious, multi-dimensional therapies that can treat or prevent skeletal diseases associated with metabolic dysfunction and inflammatory disorders are acutely needed.

Recent Findings

Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of nutrient intake, glucose metabolism, insulin production, and adipogenesis. Recent studies suggest a pivotal role for CaMKK2 in bone metabolism, fracture healing, and inflammation.

Summary

Aside from rekindling previous concepts of CaMKK2 as a potent regulator of whole-body energy homeostasis, this review emphasizes CaMKK2 as a potential therapeutic target to treat skeletal diseases that underlie metabolic conditions and inflammation.

Keywords

CaMKK2 Diabetes Diabetic osteopathy Skeletal disease Fracture healing 

Notes

Funding

This work was supported by NAIMS/NIH R01 AR068332 to US. JN was supported through a Comprehensive Musculoskeletal T32 Training Program from NIAMS/NIH (AR065971).

Compliance with Ethical Standards

Conflict of Interest

Justin N. Williams and Uma Sankar declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Yelin EH, Cisternas M. Annual all-cause and incremental direct costs for all musculoskeletal diseases in current and 2014 dollars, United States 1996-2014. The burden of musculoskeletal diseases in the united States 2017.Google Scholar
  2. 2.
    Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, et al. Denosumab or Zoledronic acid in postmenopausal women with osteoporosis previously treated with Oral bisphosphonates. J Clin Endocrinol Metab. 2016;101(8):3163–70.  https://doi.org/10.1210/jc.2016-1801.Google Scholar
  3. 3.
    Tu KN, Lie JD, Wan CKV, Cameron M, Austel AG, Nguyen JK, et al. Osteoporosis: A Review of Treatment Options. P T. 2018;43(2):92–104.Google Scholar
  4. 4.
    Jin A, Cobb J, Hansen U, Bhattacharya R, Reinhard C, Vo N, et al. The effect of long-term bisphosphonate therapy on trabecular bone strength and microcrack density. Bone Joint Res. 2017;6(10):602–9.  https://doi.org/10.1302/2046-3758.610.BJR-2016-0321.R1.Google Scholar
  5. 5.
    Miller PD, Hattersley G, Lau E, Fitzpatrick LA, Harris AG, Williams GC, et al. Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: results from the ACTIVE phase 3 trial. Bone. 2018;120:137–40.  https://doi.org/10.1016/j.bone.2018.10.015.Google Scholar
  6. 6.
    Cosman F, Eriksen EF, Recknor C, Miller PD, Guanabens N, Kasperk C, et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):503–11.  https://doi.org/10.1002/jbmr.238.Google Scholar
  7. 7.
    Cosman F, Crittenden DB, Ferrari S, Khan A, Lane NE, Lippuner K, et al. FRAME study: the Foundation effect of building bone with 1 year of Romosozumab leads to continued lower fracture risk after transition to Denosumab. J Bone Miner Res. 2018;33(7):1219–26.  https://doi.org/10.1002/jbmr.3427.Google Scholar
  8. 8.
    Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009;169(15):1395–402.  https://doi.org/10.1001/archinternmed.2009.214.Google Scholar
  9. 9.
    Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251–62.  https://doi.org/10.1038/nrm3311.Google Scholar
  10. 10.
    McCracken E, Monaghan M, Sreenivasan S. Pathophysiology of the metabolic syndrome. Clin Dermatol. 2018;36(1):14–20.  https://doi.org/10.1016/j.clindermatol.2017.09.004.Google Scholar
  11. 11.
    Fan Y, Wei F, Lang Y, Liu Y. Diabetes mellitus and risk of hip fractures: a meta-analysis. Osteoporos Int. 2016;27(1):219–28.  https://doi.org/10.1007/s00198-015-3279-7.Google Scholar
  12. 12.
    Miranda C, Giner M, Montoya MJ, Vazquez MA, Miranda MJ, Perez-Cano R. Influence of high glucose and advanced glycation end-products (ages) levels in human osteoblast-like cells gene expression. BMC Musculoskelet Disord. 2016;17:377.  https://doi.org/10.1186/s12891-016-1228-z.Google Scholar
  13. 13.
    •• Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A. Role of advanced glycation end products in cellular signaling. Redox Biol. 2014;2:411–29.  https://doi.org/10.1016/j.redox.2013.12.016. The study uggests that the skeleton is capable of regulating systemic glucose homeostasis. Google Scholar
  14. 14.
    Dirckx N, Tower RJ, Mercken EM, Vangoitsenhoven R, Moreau-Triby C, Breugelmans T, et al. Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. J Clin Invest. 2018;128(3):1087–105.  https://doi.org/10.1172/JCI97794.Google Scholar
  15. 15.
    Carafoli E. Calcium signaling: a tale for all seasons. Proc Natl Acad Sci U S A. 2002;99(3):1115–22.  https://doi.org/10.1073/pnas.032427999.Google Scholar
  16. 16.
    Clapham DE. Calcium signaling. Cell. 2007;131(6):1047–58.  https://doi.org/10.1016/j.cell.2007.11.028.Google Scholar
  17. 17.
    Marcelo KL, Means AR, York B. The ca(2+)/calmodulin/CaMKK2 Axis: Nature's metabolic CaMshaft. Trends Endocrinol Metab. 2016;27(10):706–18.  https://doi.org/10.1016/j.tem.2016.06.001.Google Scholar
  18. 18.
    Racioppi L, Means AR. Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology. J Biol Chem. 2012;287(38):31658–65.  https://doi.org/10.1074/jbc.R112.356485.Google Scholar
  19. 19.
    Green MF, Scott JW, Steel R, Oakhill JS, Kemp BE, Means AR. Ca2+/calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation. J Biol Chem. 2011;286(32):28066–79.  https://doi.org/10.1074/jbc.M111.251504.Google Scholar
  20. 20.
    Tokumitsu H, Hatano N, Fujimoto T, Yurimoto S, Kobayashi R. Generation of autonomous activity of ca(2+)/calmodulin-dependent protein kinase kinase beta by autophosphorylation. Biochemistry. 2011;50(38):8193–201.  https://doi.org/10.1021/bi201005g.Google Scholar
  21. 21.
    Green MF, Anderson KA, Means AR. Characterization of the CaMKKbeta-AMPK signaling complex. Cell Signal. 2011;23(12):2005–12.  https://doi.org/10.1016/j.cellsig.2011.07.014.Google Scholar
  22. 22.
    Dadwal UC, Chang ES, Sankar U. Androgen receptor-CaMKK2 Axis in prostate Cancer and bone microenvironment. Front Endocrinol (Lausanne). 2018;9:335.  https://doi.org/10.3389/fendo.2018.00335.Google Scholar
  23. 23.
    Lin F, Marcelo KL, Rajapakshe K, Coarfa C, Dean A, Wilganowski N, et al. The camKK2/camKIV relay is an essential regulator of hepatic cancer. Hepatology. 2015;62(2):505–20.  https://doi.org/10.1002/hep.27832.Google Scholar
  24. 24.
    Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 2008;7(5):377–88.  https://doi.org/10.1016/j.cmet.2008.02.011.Google Scholar
  25. 25.
    Rui L. Energy metabolism in the liver. Compr Physiol. 2014;4(1):177–97.  https://doi.org/10.1002/cphy.c130024.Google Scholar
  26. 26.
    Anderson KA, Lin F, Ribar TJ, Stevens RD, Muehlbauer MJ, Newgard CB, et al. Deletion of CaMKK2 from the liver lowers blood glucose and improves whole-body glucose tolerance in the mouse. Mol Endocrinol. 2012;26(2):281–91.  https://doi.org/10.1210/me.2011-1299.Google Scholar
  27. 27.
    York B, Li F, Lin F, Marcelo KL, Mao J, Dean A, et al. Pharmacological inhibition of CaMKK2 with the selective antagonist STO-609 regresses NAFLD. Sci Rep. 2017;7(1):11793.  https://doi.org/10.1038/s41598-017-12139-3.Google Scholar
  28. 28.
    Marcelo KL, Ribar T, Means CR, Tsimelzon A, Stevens RD, Ilkayeva O, et al. Research resource: roles for calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in systems metabolism. Mol Endocrinol. 2016;30(5):557–72.  https://doi.org/10.1210/me.2016-1021.Google Scholar
  29. 29.
    Tokumitsu H, Inuzuka H, Ishikawa Y, Ikeda M, Saji I, Kobayashi R. STO-609, a specific inhibitor of the ca(2+)/calmodulin-dependent protein kinase kinase. J Biol Chem. 2002;277(18):15813–8.  https://doi.org/10.1074/jbc.M201075200.Google Scholar
  30. 30.
    Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, et al. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2(1):9–19.  https://doi.org/10.1016/j.cmet.2005.05.009.Google Scholar
  31. 31.
    Lin F, Ribar TJ, Means AR. The Ca2+/calmodulin-dependent protein kinase kinase, CaMKK2, inhibits preadipocyte differentiation. Endocrinology. 2011;152(10):3668–79.  https://doi.org/10.1210/en.2011-1107.Google Scholar
  32. 32.
    Pritchard ZJ, Cary RL, Yang C, Novack DV, Voor MJ, Sankar U. Inhibition of CaMKK2 reverses age-associated decline in bone mass. Bone. 2015;75:120–7.  https://doi.org/10.1016/j.bone.2015.01.021.Google Scholar
  33. 33.
    Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17(10):1231–4.  https://doi.org/10.1038/nm.2452.Google Scholar
  34. 34.
    Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3(6):889–901.Google Scholar
  35. 35.
    Cary RL, Waddell S, Racioppi L, Long F, Novack DV, Voor MJ, et al. Inhibition of ca(2)(+)/calmodulin-dependent protein kinase kinase 2 stimulates osteoblast formation and inhibits osteoclast differentiation. J Bone Miner Res. 2013;28(7):1599–610.  https://doi.org/10.1002/jbmr.1890.Google Scholar
  36. 36.
    American Diabetes A. Economic costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018;41(5):917–28.  https://doi.org/10.2337/dci18-0007.Google Scholar
  37. 37.
    Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA. 2016;315(21):2284–91.  https://doi.org/10.1001/jama.2016.6458.Google Scholar
  38. 38.
    Maimoun L, Mura T, Leprieur E, Avignon A, Mariano-Goulart D, Sultan A. Impact of obesity on bone mass throughout adult life: influence of gender and severity of obesity. Bone. 2016;90:23–30.  https://doi.org/10.1016/j.bone.2015.11.020.Google Scholar
  39. 39.
    King LK, March L, Anandacoomarasamy A. Obesity & osteoarthritis. Indian J Med Res. 2013;138:185–93.Google Scholar
  40. 40.
    Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, et al. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab. 2011;96(6):1654–63.  https://doi.org/10.1210/jc.2011-0585.Google Scholar
  41. 41.
    Son M, Chung WJ, Oh S, Ahn H, Choi CH, Hong S, et al. Age dependent accumulation patterns of advanced glycation end product receptor (RAGE) ligands and binding intensities between RAGE and its ligands differ in the liver, kidney, and skeletal muscle. Immun Ageing. 2017;14:12.  https://doi.org/10.1186/s12979-017-0095-2.Google Scholar
  42. 42.
    Gautieri A, Passini FS, Silvan U, Guizar-Sicairos M, Carimati G, Volpi P, et al. Advanced glycation end-products: mechanics of aged collagen from molecule to tissue. Matrix Biol. 2017;59:95–108.  https://doi.org/10.1016/j.matbio.2016.09.001.Google Scholar
  43. 43.
    Cannizzaro L, Rossoni G, Savi F, Altomare A, Marinello C, Saethang T, et al. Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARgamma activation in high fructose diet-induced metabolic syndrome. Nutr Metab (Lond). 2017;14:5.  https://doi.org/10.1186/s12986-016-0149-z.Google Scholar
  44. 44.
    Tanaka K, Yamaguchi T, Kanazawa I, Sugimoto T. Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun. 2015;461(2):193–9.  https://doi.org/10.1016/j.bbrc.2015.02.091.Google Scholar
  45. 45.
    Tanaka K, Yamaguchi T, Kaji H, Kanazawa I, Sugimoto T. Advanced glycation end products suppress osteoblastic differentiation of stromal cells by activating endoplasmic reticulum stress. Biochem Biophys Res Commun. 2013;438(3):463–7.  https://doi.org/10.1016/j.bbrc.2013.07.126.Google Scholar
  46. 46.
    Davidson MB. Thiazolidinediones. N Engl J Med. 2005;352(2):205–7; author reply -7.  https://doi.org/10.1056/NEJM200501133520222.Google Scholar
  47. 47.
    Broulik PD, Sefc L, Haluzik M. Effect of PPAR-gamma agonist rosiglitazone on bone mineral density and serum adipokines in C57BL/6 male mice. Folia Biol (Praha). 2011;57(4):133–8.Google Scholar
  48. 48.
    Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009;180(1):32–9.  https://doi.org/10.1503/cmaj.080486.Google Scholar
  49. 49.
    Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355–69.  https://doi.org/10.1172/JCI40671.Google Scholar
  50. 50.
    Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253–70.  https://doi.org/10.1042/CS20110386.Google Scholar
  51. 51.
    Li Y, Su J, Sun W, Cai L, Deng Z. AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction. Int J Mol Med. 2018;41(5):2535–44.  https://doi.org/10.3892/ijmm.2018.3498.Google Scholar
  52. 52.
    Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, et al. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem. 2011;112(10):2902–9.  https://doi.org/10.1002/jcb.23206.Google Scholar
  53. 53.
    McCarthy AD, Cortizo AM, Sedlinsky C. Metformin revisited: does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabetes. 2016;7(6):122–33.  https://doi.org/10.4239/wjd.v7.i6.122.Google Scholar
  54. 54.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.  https://doi.org/10.1172/JCI19246.Google Scholar
  55. 55.
    Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11(3):234–50.  https://doi.org/10.1038/nrd3669.Google Scholar
  56. 56.
    Tsiotra PC, Boutati E, Dimitriadis G, Raptis SA. High insulin and leptin increase resistin and inflammatory cytokine production from human mononuclear cells. Biomed Res Int. 2013;2013:487081.  https://doi.org/10.1155/2013/487081.Google Scholar
  57. 57.
    Hughes FJ, Turner W, Belibasakis G, Martuscelli G. Effects of growth factors and cytokines on osteoblast differentiation. Periodontol. 2006;41:48–72.  https://doi.org/10.1111/j.1600-0757.2006.00161.x.Google Scholar
  58. 58.
    Confalone E, D'Alessio G, Furia A. IL-6 induction by TNFalpha and IL-1beta in an osteoblast-like cell line. Int J Biomed Sci. 2010;6(2):135–40.Google Scholar
  59. 59.
    Garcia-Martinez O, De Luna-Bertos E, Ramos-Torrecillas J, Manzano-Moreno FJ, Ruiz C. Repercussions of NSAIDS drugs on bone tissue: the osteoblast. Life Sci. 2015;123:72–7.  https://doi.org/10.1016/j.lfs.2015.01.009.Google Scholar
  60. 60.
    Bhattacharyya T, Levin R, Vrahas MS, Solomon DH. Nonsteroidal antiinflammatory drugs and nonunion of humeral shaft fractures. Arthritis Rheum. 2005;53(3):364–7.  https://doi.org/10.1002/art.21170.Google Scholar
  61. 61.
    Briot K, Roux C. Glucocorticoid-induced osteoporosis. RMD Open. 2015;1(1):e000014.  https://doi.org/10.1136/rmdopen-2014-000014.Google Scholar
  62. 62.
    Plotkin LI, Manolagas SC, Bellido T. Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival. Evidence for inside-out signaling leading to anoikis. J Biol Chem. 2007;282(33):24120–30.  https://doi.org/10.1074/jbc.M611435200.Google Scholar
  63. 63.
    Racioppi L, Noeldner PK, Lin F, Arvai S, Means AR. Calcium/calmodulin-dependent protein kinase kinase 2 regulates macrophage-mediated inflammatory responses. J Biol Chem. 2012;287(14):11579–91.  https://doi.org/10.1074/jbc.M111.336032.Google Scholar
  64. 64.
    Shah VN, Shah CS, Snell-Bergeon JK. Type 1 diabetes and risk of fracture: meta-analysis and review of the literature. Diabet Med. 2015;32(9):1134–42.  https://doi.org/10.1111/dme.12734.Google Scholar
  65. 65.
    Hak DJ, Fitzpatrick D, Bishop JA, Marsh JL, Tilp S, Schnettler R, et al. Delayed union and nonunions: epidemiology, clinical issues, and financial aspects. Injury. 2014;45(Suppl 2):S3–7.  https://doi.org/10.1016/j.injury.2014.04.002.Google Scholar
  66. 66.
    Griffin XL. Low intensity pulsed ultrasound for fractures of the tibial shaft. BMJ. 2016;355:i5652.  https://doi.org/10.1136/bmj.i5652.Google Scholar
  67. 67.
    Kim HS, Nam ST, Mun SH, Lee SK, Kim HW, Park YH, et al. DJ-1 controls bone homeostasis through the regulation of osteoclast differentiation. Nat Commun. 2017;8(1):1519.  https://doi.org/10.1038/s41467-017-01527-y.Google Scholar
  68. 68.
    Okonkwo UA, DiPietro LA. Diabetes and wound angiogenesis. Int J Mol Sci. 2017;18(7).  https://doi.org/10.3390/ijms18071419.
  69. 69.
    •• Tevlin R, Seo EY, Marecic O, McArdle A, Tong X, Zimdahl B, et al. Pharmacological rescue of diabetic skeletal stem cell niches. Sci Transl Med. 2017;9(372).  https://doi.org/10.1126/scitranslmed.aag2809. Demonstrates a potential mechanism for type 2 diabetes to impair the skeletal stem cell response during bone fracture healing.
  70. 70.
    •• Lin YC, Roffler SR, Yan YT, Yang RB. Disruption of Scube2 Impairs Endochondral Bone Formation. J Bone Miner Res. 2015;30(7):1255–67.  https://doi.org/10.1002/jbmr.2451. This study reveals inhibition of CaMKK2 promotes efficient bone fracture healing through modulation of IHH. Google Scholar
  71. 71.
    Williams JN, Kambrath AV, Patel RB, Kang KS, Mevel E, Li Y, et al. Inhibition of CaMKK2 enhances fracture healing by stimulating Indian hedgehog signaling and accelerating endochondral ossification. J Bone Miner Res. 2018;33(5):930–44.  https://doi.org/10.1002/jbmr.3379.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisUSA

Personalised recommendations