Role of Dkk2 in the Muscle/bone Interaction of Androgen-Deficient Mice

Abstract

Androgen deficiency is known to cause both osteoporosis and sarcopenia. Myokines, humoral factors secreted from the skeletal muscles, have recently been getting attention as the key factors related to the interactions between muscle and bone. Dickkopf (Dkk) 2 is known as an inhibitor of canonical Wnt/β-catenin signaling, and Wnt/β-catenin signaling is crucial for the maintenance of muscle and bone. The present study was therefore performed to investigate the roles of Dkk2 in the alterations of muscle and bone of androgen-deficient mice with orchidectomy (ORX). ORX significantly enhanced Dkk2 mRNA levels, but not other Dkks and secreted frizzled related proteins, in the soleus muscles of mice. Moreover, ORX enhanced serum Dkk2 levels, but not Dkk2 mRNA levels in the tibial bone tissues, the white adipose tissues and liver of mice. In simple regression analyses, serum Dkk2 levels were negatively related to trabecular bone mineral density at the tibias in mice employed in the experiments. In vitro experiments, testosterone suppressed Dkk2 mRNA levels in mouse muscle C2C12 cells. In conclusion, we showed that androgen deficiency enhances Dkk2 expression and secretion in the muscles of mice. Dkk2 might be involved in androgen deficiency-induced muscle wasting and osteopenia as a myokine linking muscle to bone.

Key words

androgen deficiency - Dkk2 - muscle wasting - osteopenia

• References

• 1 Watts NB, Adler RA, Bilezikian JP. et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 1802-1822
• 2 Khosla S. Update in male osteoporosis. J Clin Endocrinol Metab 2010; 95: 3-10
• 3 Almeida M, Laurent MR, Dubois V. et al. Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 2017; 97: 135-187
• 4 Carson JA, Manolagas SC. Effects of sex steroids on bones and muscles: Similarities, parallels, and putative interactions in health and disease. Bone 2015; 80: 67-78
• 5 Shahinian VB, Kuo YF, Freeman JL. et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352: 154-164
• 6 Russell PK, Clarke MV, Cheong K. et al. Androgen receptor action in osteoblasts in male mice is dependent on their stage of maturation. J Bone Miner Res 2015; 30: 809-823
• 7 Sinnesael M, Claessens F, Laurent M. et al. Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes. J Bone Miner Res 2012; 27: 2535-2543
• 8 Skinner JW, Otzel DM, Bowser A. et al. Muscular responses to testosterone replacement vary by administration route: A systematic review and meta-analysis. J Cachexia Sarcopenia Muscle 2018; 9: 465-481
• 9 Iemura S, Kawao N, Okumoto K. et al. Role of irisin in androgen-deficient muscle wasting and osteopenia in mice. J Bone Miner Metab 2020; 38: 161-171
• 10 Kawao N, Kaji H. Interactions between muscle tissues and bone metabolism. J Cell Biochem 2015; 116: 687-695
• 11 Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 2013; 19: 179-192
• 12 Mumford PW, Romero MA, Mao X. et al. Cross talk between androgen and Wnt signaling potentially contributes to age-related skeletal muscle atrophy in rats. J Appl Physiol (1985) 2018; 486-494
• 13 Li J, Sarosi I, Cattley RC. et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 2006; 39: 754-766
• 14 Morvan F, Boulukos K, Clement-Lacroix P. et al. Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 2006; 21: 934-945
• 15 Tian E, Zhan F, Walker R. et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 2483-2494
• 16 Ahmed SF, Fouda N, Abbas AA. Serum dickkopf-1 level in postmenopausal females: Correlation with bone mineral density and serum biochemical markers. J Osteoporos 2013; 2013: 460210
• 17 Kawao N, Morita H, Iemura S. et al. Roles of Dkk2 in the linkage from muscle to bone during mechanical unloading in mice. Int J Mol Sci 2020; 21: 2547
• 18 Chan TF, Couchourel D, Abed E. et al. Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. J Bone Miner Res 2011; 26: 1399-1410
• 19 Li X, Liu P, Liu W. et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat Genet 2005; 37: 945-952
• 20 Holdsworth G, Roberts SJ, Ke HZ. Novel actions of sclerostin on bone. J Mol Endocrinol 2019; 62: R167-R185
• 21 Rudnicki MA, Williams BO. Wnt signaling in bone and muscle. Bone 2015; 80: 60-66
• 22 Chen L, Wang K, Shao Y. et al. Structural insight into the mechanisms of Wnt signaling antagonism by Dkk. J Biol Chem 2008; 283: 23364-23370
• 23 van der Horst G, van der Werf SM, Farih-Sips H. et al. Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells. J Bone Miner Res 2005; 20: 1867-1877
• 24 Li L, Mao J, Sun L. et al. Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. J Biol Chem 2002; 277: 5977-5981
• 25 Mao B, Niehrs C. Kremen2 modulates Dickkopf2 activity during Wnt/LRP6 signaling. Gene 2003; 302: 179-183
• 26 Kawao N, Moritake A, Tatsumi K. et al. Roles of irisin in the linkage from muscle to bone during mechanical unloading in mice. Calcif Tissue Int 2018; 103: 24-34
• 27 Gharahdaghi N, Rudrappa S, Brook MS. et al. Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men. J Cachexia Sarcopenia Muscle 2019; 10: 1276-1294
• 28 Ferry A, Schuh M, Parlakian A. et al. Myofiber androgen receptor promotes maximal mechanical overload-induced muscle hypertrophy and fiber type transition in male mice. Endocrinology 2014; 155: 4739-4748