CaMKK2 Signaling in Metabolism and Skeletal Disease: a New Axis with Therapeutic Potential
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.
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.
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.
KeywordsCaMKK2 Diabetes Diabetic osteopathy Skeletal disease Fracture healing
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.
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 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.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.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.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.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
- 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
- 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
- 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
- 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
- 39.King LK, March L, Anandacoomarasamy A. Obesity & osteoarthritis. Indian J Med Res. 2013;138:185–93.Google Scholar
- 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
- 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.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
- 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
- 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
- 68.Okonkwo UA, DiPietro LA. Diabetes and wound angiogenesis. Int J Mol Sci. 2017;18(7). https://doi.org/10.3390/ijms18071419.
- 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.