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Metabolic Health and Disease: A Role of Osteokines?

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Abstract

Maintenance of skeletal health is tightly regulated by osteocytes, osteoblasts, and osteoclasts via coordinated secretion of bone-derived factors, termed osteokines. Disruption of this coordinated process due to aging and metabolic disease promotes loss of bone mass and increased risk of fracture. Indeed, growing evidence demonstrates that metabolic diseases, including type 2 diabetes, liver disease and cancer are accompanied by bone loss and altered osteokine levels. With the persistent prevalence of cancer and the growing epidemic of metabolic disorders, investigations into the role of inter-tissue communication during disease progression are on the rise. While osteokines are imperative for bone homeostasis, work from us and others have identified that osteokines possess endocrine functions, exerting effects on distant tissues including skeletal muscle and liver. In this review we first discuss the prevalence of bone loss and osteokine alterations in patients with type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cirrhosis, and cancer. We then discuss the effects of osteokines in mediating skeletal muscle and liver homeostasis, including RANKL, sclerostin, osteocalcin, FGF23, PGE2, TGF-β, BMPs, IGF-1 and PTHrP. To better understand how inter-tissue communication contributes to disease progression, it is essential that we include the bone secretome and the systemic roles of osteokines.

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References

  1. Araujo J, Cai J, Stevens J (2019) Prevalence of optimal metabolic health in American adults: National health and nutrition examination survey 2009–2016. Metab Syndr Relat Disord 17:46–52

    Article  PubMed  Google Scholar 

  2. Rafei A, Elliott MR, Jones RE, Riosmena F, Cunningham SA, Mehta NK (2022) Obesity incidence in U.S. children and young adults: a pooled analysis. Am J Prev Med 63:51–59

    Article  PubMed  PubMed Central  Google Scholar 

  3. Noubiap JJ, Nansseu JR, Lontchi-Yimagou E, Nkeck JR, Nyaga UF, Ngouo AT, Tounouga DN, Tianyi FL, Foka AJ, Ndoadoumgue AL, Bigna JJ (2022) Geographic distribution of metabolic syndrome and its components in the general adult population: a meta-analysis of global data from 28 million individuals. Diabetes Res Clin Pract 188:109924

    Article  CAS  PubMed  Google Scholar 

  4. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M (2016) Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73–84

    Article  PubMed  Google Scholar 

  5. Kalra A, Yetiskul E, Wehrle CJ, Tuma F (2022) Physiology, liver. StatPearls, Treasure Island

    Google Scholar 

  6. Argiles JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Manas L (2016) Skeletal muscle regulates metabolism via interorgan crosstalk: roles in health and disease. J Am Med Dir Assoc 17:789–796

    Article  PubMed  Google Scholar 

  7. Jung TW, Yoo HJ, Choi KM (2016) Implication of hepatokines in metabolic disorders and cardiovascular diseases. BBA Clin 5:108–113

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ke Y, Xu C, Lin J, Li Y (2019) Role of hepatokines in non-alcoholic fatty liver disease. J Transl Int Med 7:143–148

    Article  PubMed  PubMed Central  Google Scholar 

  9. Pin F, Bonewald LF, Bonetto A (2021) Role of myokines and osteokines in cancer cachexia. Exp Biol Med (Maywood) 246:2118–2127

    Article  CAS  PubMed  Google Scholar 

  10. Zaheer S, LeBoff MS (2000) Osteoporosis: prevention and treatment. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Hofland J, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP (eds) Endotext. MDText.com. Inc., South Dartmouth

    Google Scholar 

  11. Sarafrazi N, Wambogo EA, Shepherd JA (2021) Osteoporosis or low bone mass in older adults: United States, 2017–2018. NCHS Data Brief, pp 1–8

    Book  Google Scholar 

  12. Liu X, Chen F, Liu L, Zhang Q (2023) Prevalence of osteoporosis in patients with diabetes mellitus: a systematic review and meta-analysis of observational studies. BMC Endocr Disord 23:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu B, Fu Z, Wang X, Zhou P, Yang Q, Jiang Y, Zhu D (2022) A narrative review of diabetic bone disease: characteristics, pathogenesis, and treatment. Front Endocrinol (Lausanne) 13:1052592

    Article  PubMed  Google Scholar 

  14. Pan B, Cai J, Zhao P, Liu J, Fu S, Jing G, Niu Q, Li Q (2022) Relationship between prevalence and risk of osteoporosis or osteoporotic fracture with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Osteoporos Int 33:2275–2286

    Article  PubMed  Google Scholar 

  15. Liu J, Tang Y, Feng Z, Chen Y, Zhang X, Xia Y, Geng B (2023) Metabolic associated fatty liver disease and bone mineral density: a cross-sectional study of the National health and nutrition examination survey 2017–2018. Osteoporos Int 34:713

    Article  CAS  PubMed  Google Scholar 

  16. Kang J, Gopakumar H, Puli SR (2023) Prevalence of osteoporosis in cirrhosis: a systematic review and meta-analysis. Cureus 15:e33721

    PubMed  PubMed Central  Google Scholar 

  17. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE (2011) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12:489–495

    Article  PubMed  Google Scholar 

  18. Hung YC, Yeh LS, Chang WC, Lin CC, Kao CH (2002) Prospective study of decreased bone mineral density in patients with cervical cancer without bone metastases: a preliminary report. Jpn J Clin Oncol 32:422–424

    Article  PubMed  Google Scholar 

  19. Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T (1999) A high incidence of vertebral fracture in women with breast cancer. Br J Cancer 79:1179–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ye C, Leslie WD (2023) Fracture risk and assessment in adults with cancer. Osteoporos Int 34:449–466

    Article  PubMed  Google Scholar 

  21. Wu D, Wu XD, Zhou X, Huang W, Luo C, Liu Y (2021) Bone mineral density, osteopenia, osteoporosis, and fracture risk in patients with atopic dermatitis: a systematic review and meta-analysis. Ann Transl Med 9:40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Buenzli PR, Sims NA (2015) Quantifying the osteocyte network in the human skeleton. Bone 75:144–150

    Article  CAS  PubMed  Google Scholar 

  23. Xiong J, Piemontese M, Onal M, Campbell J, Goellner JJ, Dusevich V, Bonewald L, Manolagas SC, O’Brien CA (2015) Osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling bone. PLoS ONE 10:e0138189

    Article  PubMed  PubMed Central  Google Scholar 

  24. Xiong J, O’Brien CA (2012) Osteocyte RANKL: new insights into the control of bone remodeling. J Bone Miner Res 27:499–505

    Article  CAS  PubMed  Google Scholar 

  25. Ono T, Hayashi M, Sasaki F, Nakashima T (2020) RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen 40:2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lv X, Zou L, Zhang X, Zhang X, Lai H, Shi J (2022) Effects of diabetes/hyperglycemia on peri-implant biomarkers and clinical and radiographic outcomes in patients with dental implant restorations: a systematic review and meta-analysis. Clin Oral Implants Res 33:1183–1198

    Article  CAS  PubMed  Google Scholar 

  27. Kiechl S, Wittmann J, Giaccari A, Knoflach M, Willeit P, Bozec A, Moschen AR, Muscogiuri G, Sorice GP, Kireva T, Summerer M, Wirtz S, Luther J, Mielenz D, Billmeier U, Egger G, Mayr A, Oberhollenzer F, Kronenberg F, Orthofer M, Penninger JM, Meigs JB, Bonora E, Tilg H, Willeit J, Schett G (2013) Blockade of receptor activator of nuclear factor-kappaB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med 19:358–363

    Article  CAS  PubMed  Google Scholar 

  28. Venuraju SM, Yerramasu A, Corder R, Lahiri A (2010) Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. J Am Coll Cardiol 55:2049–2061

    Article  CAS  PubMed  Google Scholar 

  29. Lu N, Shan C, Fu JR, Zhang Y, Wang YY, Zhu YC, Yu J, Cai J, Li SX, Tao T, Liu W (2023) RANKL is independently associated with increased risks of non-alcoholic fatty liver disease in Chinese women with PCOS: a cross-sectional study. J Clin Med 12:20

    Article  CAS  Google Scholar 

  30. Moschen AR, Kaser A, Stadlmann S, Millonig G, Kaser S, Muhllechner P, Habior A, Graziadei I, Vogel W, Tilg H (2005) The RANKL/OPG system and bone mineral density in patients with chronic liver disease. J Hepatol 43:973–983

    Article  PubMed  Google Scholar 

  31. Kiechl S, Schramek D, Widschwendter M, Fourkala EO, Zaikin A, Jones A, Jaeger B, Rack B, Janni W, Scholz C, Willeit J, Weger S, Mayr A, Teschendorff A, Rosenthal A, Fraser L, Philpott S, Dubeau L, Keshtgar M, Roylance R, Jacobs IJ, Menon U, Schett G, Penninger JM (2017) Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer. Oncotarget 8:3811–3825

    Article  PubMed  Google Scholar 

  32. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pin F, Jones AJ, Huot JR, Narasimhan A, Zimmers TA, Bonewald LF, Bonetto A (2022) RANKL blockade reduces cachexia and bone loss induced by non-metastatic ovarian cancer in mice. J Bone Miner Res 37:381–396

    Article  CAS  PubMed  Google Scholar 

  34. Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Löwik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. Faseb j 19:1842–1844

    Article  CAS  PubMed  Google Scholar 

  35. Robling AG, Bonewald LF (2020) The osteocyte: new insights. Annu Rev Physiol 82:485–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gennari L, Merlotti D, Valenti R, Ceccarelli E, Ruvio M, Pietrini MG, Capodarca C, Franci MB, Campagna MS, Calabro A, Cataldo D, Stolakis K, Dotta F, Nuti R (2012) Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes. J Clin Endocrinol Metab 97:1737–1744

    Article  CAS  PubMed  Google Scholar 

  37. Garcia-Martin A, Rozas-Moreno P, Reyes-Garcia R, Morales-Santana S, Garcia-Fontana B, Garcia-Salcedo JA, Munoz-Torres M (2012) Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 97:234–241

    Article  CAS  PubMed  Google Scholar 

  38. Wu Y, Xu SY, Liu SY, Xu L, Deng SY, He YB, Xian SC, Liu YH, Ni GX (2017) Upregulated serum sclerostin level in the T2DM patients with femur fracture inhibits the expression of bone formation/remodeling-associated biomarkers via antagonizing Wnt signaling. Eur Rev Med Pharmacol Sci 21:470–478

    CAS  PubMed  Google Scholar 

  39. Rhee Y, Kim WJ, Han KJ, Lim SK, Kim SH (2014) Effect of liver dysfunction on circulating sclerostin. J Bone Miner Metab 32:545–549

    Article  CAS  PubMed  Google Scholar 

  40. Wakolbinger R, Muschitz C, Wallwitz J, Bodlaj G, Feichtinger X, Schanda JE, Resch H, Baierl A, Pietschmann P (2020) Serum levels of sclerostin reflect altered bone microarchitecture in patients with hepatic cirrhosis. Wien Klin Wochenschr 132:19–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhou F, Wang Y, Li Y, Tang M, Wan S, Tian H, Chen X (2021) Decreased sclerostin secretion in humans and mice with nonalcoholic fatty liver disease. Front Endocrinol (Lausanne) 12:707505

    Article  PubMed  Google Scholar 

  42. Polyzos SA, Anastasilakis AD, Kountouras J, Makras P, Papatheodorou A, Kokkoris P, Sakellariou GT, Terpos E (2016) Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease. J Bone Miner Metab 34:447–456

    Article  CAS  PubMed  Google Scholar 

  43. Yavropoulou MP, van Lierop AH, Hamdy NA, Rizzoli R, Papapoulos SE (2012) Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. Bone 51:153–157

    Article  CAS  PubMed  Google Scholar 

  44. Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E, Delimpasi S, Pouli A, Meletis J, Kastritis E, Zervas K, Dimopoulos MA (2012) Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. Int J Cancer 131:1466–1471

    Article  CAS  PubMed  Google Scholar 

  45. Zhu M, Liu C, Li S, Zhang S, Yao Q, Song Q (2017) Sclerostin induced tumor growth, bone metastasis and osteolysis in breast cancer. Sci Rep 7:11399

    Article  PubMed  PubMed Central  Google Scholar 

  46. Hesse E, Schroder S, Brandt D, Pamperin J, Saito H, Taipaleenmaki H (2019) Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI Insight. https://doi.org/10.1172/jci.insight.125543

    Article  PubMed  PubMed Central  Google Scholar 

  47. Bonewald L (2019) Use it or lose it to age: a review of bone and muscle communication. Bone 120:212–218

    Article  PubMed  Google Scholar 

  48. Zanatta LC, Boguszewski CL, Borba VZ, Kulak CA (2014) Osteocalcin, energy and glucose metabolism. Arq Bras Endocrinol Metabol 58:444–451

    Article  PubMed  Google Scholar 

  49. Zeng H, Ge J, Xu W, Ma H, Chen L, Xia M, Pan B, Lin H, Wang S, Gao X (2021) Type 2 diabetes is causally associated with reduced serum osteocalcin: a genomewide association and mendelian randomization study. J Bone Miner Res 36:1694–1707

    Article  CAS  PubMed  Google Scholar 

  50. Nasser MI, Stidsen JV, Hojlund K, Nielsen JS, Eastell R, Frost M (2023) Low bone turnover associates with lower insulin sensitivity in newly diagnosed drug-naive persons with type 2 diabetes. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgad043

    Article  PubMed  PubMed Central  Google Scholar 

  51. Yilmaz Y, Kurt R, Eren F, Imeryuz N (2011) Serum osteocalcin levels in patients with nonalcoholic fatty liver disease: association with ballooning degeneration. Scand J Clin Lab Invest 71:631–636

    Article  CAS  PubMed  Google Scholar 

  52. Yang HJ, Shim SG, Ma BO, Kwak JY (2016) Association of nonalcoholic fatty liver disease with bone mineral density and serum osteocalcin levels in Korean men. Eur J Gastroenterol Hepatol 28:338–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Luo YQ, Ma XJ, Hao YP, Pan XP, Xu YT, Xiong Q, Bao YQ, Jia WP (2015) Inverse relationship between serum osteocalcin levels and nonalcoholic fatty liver disease in postmenopausal Chinese women with normal blood glucose levels. Acta Pharmacol Sin 36:1497–1502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fang D, Yin H, Ji X, Sun H, Zhao X, Bi Y, Gu T (2022) Low levels of osteocalcin, but not CTX or P1NP, are associated with nonalcoholic hepatic steatosis and steatohepatitis. Diabetes Metab 49:101397

    Article  PubMed  Google Scholar 

  55. Karapanagiotou EM, Terpos E, Dilana KD, Alamara C, Gkiozos I, Polyzos A, Syrigos KN (2010) Serum bone turnover markers may be involved in the metastatic potential of lung cancer patients. Med Oncol 27:332–338

    Article  CAS  PubMed  Google Scholar 

  56. Bayrak SB, Ceylan E, Serter M, Karadag F, Demir E, Cildag O (2012) The clinical importance of bone metabolic markers in detecting bone metastasis of lung cancer. Int J Clin Oncol 17:112–118

    Article  CAS  PubMed  Google Scholar 

  57. Ahmeid MS, Hassan WN, Awa NA (2022) Evaluation of the serum level of osteocalcin in breast cancer patients, and its association with estrogen and progesterone receptors. Egypt J Hosp Med 89:6209–6213

    Article  Google Scholar 

  58. Xia M, Rong S, Zhu X, Yan H, Chang X, Sun X, Zeng H, Li X, Zhang L, Chen L, Wu L, Ma H, Hu Y, He W, Gao J, Pan B, Hu X, Lin H, Bian H, Gao X (2021) Osteocalcin and non-alcoholic fatty liver disease: lessons from two population-based cohorts and animal models. J Bone Miner Res 36:712–728

    Article  CAS  PubMed  Google Scholar 

  59. Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res 26:229–238

    Article  CAS  PubMed  Google Scholar 

  60. He X, Hu X, Ma X, Su H, Ying L, Peng J, Pan X, Bao Y, Zhou J, Jia W (2017) Elevated serum fibroblast growth factor 23 levels as an indicator of lower extremity atherosclerotic disease in Chinese patients with type 2 diabetes mellitus. Cardiovasc Diabetol 16:77

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gateva A, Assyov Y, Tsakova A, Kamenov Z (2019) Prediabetes is characterized by higher FGF23 levels and higher prevalence of vitamin D deficiency compared to normal glucose tolerance subjects. Horm Metab Res 51:106–111

    Article  CAS  PubMed  Google Scholar 

  62. He X, Shen Y, Ma X, Ying L, Peng J, Pan X, Bao Y, Zhou J (2018) The association of serum FGF23 and non-alcoholic fatty liver disease is independent of vitamin D in type 2 diabetes patients. Clin Exp Pharmacol Physiol 45:668–674

    Article  CAS  PubMed  Google Scholar 

  63. Stewart I, Roddie C, Gill A, Clarkson A, Mirams M, Coyle L, Ward C, Clifton-Bligh P, Robinson BG, Mason RS, Clifton-Bligh RJ (2006) Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone 39:369–376

    Article  CAS  PubMed  Google Scholar 

  64. Tebben PJ, Kalli KR, Cliby WA, Hartmann LC, Grande JP, Singh RJ, Kumar R (2005) Elevated fibroblast growth factor 23 in women with malignant ovarian tumors. Mayo Clin Proc 80:745–751

    Article  CAS  PubMed  Google Scholar 

  65. Cekin R et al (2020) The clinical importance of fibroblast growth factor 23 on breast cancer patients. J Med Invest 4:471–476

    Google Scholar 

  66. Feng S, Wang J, Zhang Y, Creighton CJ, Ittmann M (2015) FGF23 promotes prostate cancer progression. Oncotarget 6:17291–17301

    Article  PubMed  PubMed Central  Google Scholar 

  67. Mo C, Romero-Suarez S, Bonewald L, Johnson M, Brotto M (2012) Prostaglandin E2: from clinical applications to its potential role in bone- muscle crosstalk and myogenic differentiation. Recent Pat Biotechnol 6:223–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pawelzik SC, Avignon A, Idborg H, Boegner C, Stanke-Labesque F, Jakobsson PJ, Sultan A, Back M (2019) Urinary prostaglandin D(2) and E(2) metabolites associate with abdominal obesity, glucose metabolism, and triglycerides in obese subjects. Prostaglandins Other Lipid Mediat 145:106361

    Article  CAS  PubMed  Google Scholar 

  69. Fenske RJ, Weeks AM, Daniels M, Nall R, Pabich S, Brill AL, Peter DC, Punt M, Cox ED, Davis DB, Kimple ME (2022) Plasma prostaglandin E(2) metabolite levels predict type 2 diabetes status and one-year therapeutic response independent of clinical markers of inflammation. Metabolites 12:1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Henkel J, Coleman CD, Schraplau A, Johrens K, Weiss TS, Jonas W, Schurmann A, Puschel GP (2018) Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model. Sci Rep 8:16127

    Article  PubMed  PubMed Central  Google Scholar 

  71. Loomba R, Quehenberger O, Armando A, Dennis EA (2015) Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis. J Lipid Res 56:185–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Goodla L, Xue X (2022) The role of inflammatory mediators in colorectal cancer hepatic metastasis. Cells 11:2313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P (2011) Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood 118:5498–5505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang F, Wang M, Yin H, Long Z, Zhu L, Yu H, Sun H, Bi H, Li S, Zhao Y, Dong X, Zhou J (2021) Association between plasma prostaglandin E2 level and colorectal cancer. Eur J Cancer Prev 30:59–68

    Article  CAS  PubMed  Google Scholar 

  75. Bonewald LF, Mundy GR (1990) Role of transforming growth factor-beta in bone remodeling. Clin Orthop Relat Res 1990:261–276

    Google Scholar 

  76. Crane JL, Xian L, Cao X (2016) Role of TGF-β signaling in coupling bone remodeling. Methods Mol Biol 1344:287–300

    Article  CAS  PubMed  Google Scholar 

  77. Herrera B, Dooley S, Breitkopf-Heinlein K (2014) Potential roles of bone morphogenetic protein (BMP)-9 in human liver diseases. Int J Mol Sci 15:5199–5220

    Article  PubMed  PubMed Central  Google Scholar 

  78. Katagiri T, Watabe T (2016) Bone morphogenetic proteins. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a021899

    Article  PubMed  PubMed Central  Google Scholar 

  79. Herrera B, Addante A, Sánchez A (2017) BMP signalling at the crossroad of liver fibrosis and regeneration. Int J Mol Sci 19:39

    Article  PubMed  PubMed Central  Google Scholar 

  80. Qiao YC, Chen YL, Pan YH, Ling W, Tian F, Zhang XX, Zhao HL (2017) Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 96:e6583

    Article  CAS  PubMed  Google Scholar 

  81. Tarantino G, Conca P, Riccio A, Tarantino M, Di Minno MN, Chianese D, Pasanisi F, Contaldo F, Scopacasa F, Capone D (2008) Enhanced serum concentrations of transforming growth factor-beta1 in simple fatty liver: is it really benign? J Transl Med 6:72

    Article  PubMed  PubMed Central  Google Scholar 

  82. Duan Y, Pan X, Luo J, Xiao X, Li J, Bestman PL, Luo M (2022) Association of inflammatory cytokines with non-alcoholic fatty liver disease. Front Immunol 13:880298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Fabregat I, Moreno-Caceres J, Sanchez A, Dooley S, Dewidar B, Giannelli G, Ten Dijke P, Consortium IL (2016) TGF-beta signalling and liver disease. FEBS J 283:2219–2232

    Article  CAS  PubMed  Google Scholar 

  84. Lu WQ, Qiu JL, Huang ZL, Liu HY (2016) Enhanced circulating transforming growth factor beta 1 is causally associated with an increased risk of hepatocellular carcinoma: a mendelian randomization meta-analysis. Oncotarget 7:84695–84704

    Article  PubMed  PubMed Central  Google Scholar 

  85. Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Liu ZY, Zhang YQ, Pan X, Li GC (2017) High TGF-beta1 expression predicts poor disease prognosis in hepatocellular carcinoma patients. Oncotarget 8:34387–34397

    Article  PubMed  PubMed Central  Google Scholar 

  86. Teicher BA (2001) Malignant cells, directors of the malignant process: role of transforming growth factor-beta. Cancer Metastasis Rev 20:133–143

    Article  CAS  PubMed  Google Scholar 

  87. Luo Y, Li L, Xu X, Wu T, Yang M, Zhang C, Mou H, Zhou T, Jia Y, Cai C, Liu H, Yang G, Zhang X (2017) Decreased circulating BMP-9 levels in patients with Type 2 diabetes is a signature of insulin resistance. Clin Sci (Lond) 131:239–246

    Article  CAS  PubMed  Google Scholar 

  88. Zhang JM, Yu RQ, Wu FZ, Qiao L, Wu XR, Fu YJ, Liang YF, Pang Y, Xie CY (2021) BMP-2 alleviates heart failure with type 2 diabetes mellitus and doxorubicin-induced AC16 cell injury by inhibiting NLRP3 inflammasome-mediated pyroptosis. Exp Ther Med 22:897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhang M, Sara JD, Wang FL, Liu LP, Su LX, Zhe J, Wu X, Liu JH (2015) Increased plasma BMP-2 levels are associated with atherosclerosis burden and coronary calcification in type 2 diabetic patients. Cardiovasc Diabetol 14:64

    Article  PubMed  PubMed Central  Google Scholar 

  90. Maranon P, Fernandez-Garcia CE, Isaza SC, Rey E, Gallego-Duran R, Montero-Vallejo R, de Cia JR, Ampuero J, Romero-Gomez M, Garcia-Monzon C, Gonzalez-Rodriguez A (2022) Bone morphogenetic protein 2 is a new molecular target linked to non-alcoholic fatty liver disease with potential value as non-invasive screening tool. Biomark Res 10:35

    Article  PubMed  PubMed Central  Google Scholar 

  91. Tacke F, Gabele E, Bataille F, Schwabe RF, Hellerbrand C, Klebl F, Straub RH, Luedde T, Manns MP, Trautwein C, Brenner DA, Scholmerich J, Schnabl B (2007) Bone morphogenetic protein 7 is elevated in patients with chronic liver disease and exerts fibrogenic effects on human hepatic stellate cells. Dig Dis Sci 52:3404–3415

    Article  CAS  PubMed  Google Scholar 

  92. Li P, Li Y, Zhu L, Yang Z, He J, Wang L, Shang Q, Pan H, Wang H, Ma X, Li B, Fan X, Ge S, Jia R, Zhang H (2018) Targeting secreted cytokine BMP9 gates the attenuation of hepatic fibrosis. Biochim Biophys Acta Mol Basis Dis 1864:709–720

    Article  CAS  PubMed  Google Scholar 

  93. Mano Y, Yoshio S, Shoji H, Tomonari S, Aoki Y, Aoyanagi N, Okamoto T, Matsuura Y, Osawa Y, Kimura K, Yugawa K, Wang H, Oda Y, Yoshizumi T, Maehara Y, Kanto T (2019) Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma. J Gastroenterol 54:1007–1018

    Article  CAS  PubMed  Google Scholar 

  94. Sjögren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Törnell J, Isaksson OG, Jansson JO, Ohlsson C (1999) Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci U S A 96:7088–7092

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wang E, Wang J, Chin E, Zhou J, Bondy CA (1995) Cellular patterns of insulin-like growth factor system gene expression in murine chondrogenesis and osteogenesis. Endocrinology 136:2741–2751

    Article  CAS  PubMed  Google Scholar 

  96. Lean JM, Mackay AG, Chow JW, Chambers TJ (1996) Osteocytic expression of mRNA for c-fos and IGF-I: an immediate early gene response to an osteogenic stimulus. Am J Physiol 270:E937-945

    CAS  PubMed  Google Scholar 

  97. Sheng MH, Zhou XD, Bonewald LF, Baylink DJ, Lau KH (2013) Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice. Bone 52:133–144

    Article  CAS  PubMed  Google Scholar 

  98. Govoni KE (2012) Insulin-like growth factor-I molecular pathways in osteoblasts: potential targets for pharmacological manipulation. Curr Mol Pharmacol 5:143–152

    Article  CAS  PubMed  Google Scholar 

  99. Lv F, Cai X, Zhang R, Zhou L, Zhou X, Han X, Ji L (2021) Sex-specific associations of serum insulin-like growth factor-1 with bone density and risk of fractures in Chinese patients with type 2 diabetes. Osteoporos Int 32:1165–1173

    Article  CAS  PubMed  Google Scholar 

  100. Adamek A, Kasprzak A (2018) Insulin-like growth factor (IGF) system in liver diseases. Int J Mol Sci 19:1308

    Article  PubMed  PubMed Central  Google Scholar 

  101. Knuppel A, Fensom GK, Watts EL, Gunter MJ, Murphy N, Papier K, Perez-Cornago A, Schmidt JA, Smith Byrne K, Travis RC, Key TJ (2020) Circulating insulin-like growth factor-I concentrations and risk of 30 cancers: prospective analyses in UK biobank. Cancer Res 80:4014–4021

    Article  CAS  PubMed  Google Scholar 

  102. Wysolmerski JJ (2012) Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab 97:2947–2956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lai NK, Martinez D (2019) Physiological roles of parathyroid hormone-related protein. Acta Biomed 90:510–516

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Martin TJ (2005) Osteoblast-derived PTHrP is a physiological regulator of bone formation. J Clin Invest 115:2322–2324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Jähn K, Kelkar S, Zhao H, Xie Y, Tiede-Lewis LM, Dusevich V, Dallas SL, Bonewald LF (2017) Osteocytes acidify their microenvironment in response to PTHrP in vitro and in lactating mice in vivo. J Bone Miner Res 32:1761–1772

    Article  PubMed  Google Scholar 

  106. Roca-Rodriguez MM, El Bekay R, Garrido-Sanchez L, Gomez-Serrano M, Coin-Araguez L, Oliva-Olivera W, Lhamyani S, Clemente-Postigo M, Garcia-Santos E, de Luna DR, Yubero-Serrano EM, Fernandez Real JM, Peral B, Tinahones FJ (2015) Parathyroid hormone-related protein, human adipose-derived stem cells adipogenic capacity and healthy obesity. J Clin Endocrinol Metab 100:E826-835

    Article  CAS  PubMed  Google Scholar 

  107. Romero M, Ortega A, Olea N, Arenas MI, Izquierdo A, Bover J, Esbrit P, Bosch RJ (2013) Novel role of parathyroid hormone-related protein in the pathophysiology of the diabetic kidney: evidence from experimental and human diabetic nephropathy. J Diabetes Res 2013:162846

    Article  PubMed  PubMed Central  Google Scholar 

  108. Legakis I, Mantouridis T (2009) Positive correlation of PTH-related peptide with glucose in type 2 diabetes. Exp Diabetes Res 2009:291027

    Article  PubMed  PubMed Central  Google Scholar 

  109. Fabrega E, Rivero M, Pons-Romero F, Garcia-Unzueta MT, Amado JA (2000) Parathyroid hormone-related protein in liver cirrhosis. Dig Dis Sci 45:703

    Article  CAS  PubMed  Google Scholar 

  110. Edwards CM, Johnson RW (2021) From good to bad: the opposing effects of PTHrP on tumor growth, dormancy, and metastasis throughout cancer progression. Front Oncol 11:644303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hong N, Yoon HJ, Lee YH, Kim HR, Lee BW, Rhee Y, Kang ES, Cha BS, Lee HC (2016) Serum PTHrP predicts weight loss in cancer patients independent of hypercalcemia, inflammation, and tumor burden. J Clin Endocrinol Metab 101:1207–1214

    Article  CAS  PubMed  Google Scholar 

  112. Dufresne SS, Dumont NA, Boulanger-Piette A, Fajardo VA, Gamu D, Kake-Guena SA, David RO, Bouchard P, Lavergne É, Penninger JM, Pape PC, Tupling AR, Frenette J (2016) Muscle RANK is a key regulator of Ca2+ storage, SERCA activity, and function of fast-twitch skeletal muscles. Am J Physiol Cell Physiol 310:C663-672

    Article  PubMed  PubMed Central  Google Scholar 

  113. Hamoudi D, Bouredji Z, Marcadet L, Yagita H, Landry LB, Argaw A, Frenette J (2020) Muscle weakness and selective muscle atrophy in osteoprotegerin-deficient mice. Hum Mol Genet 29:483–494

    Article  CAS  PubMed  Google Scholar 

  114. Hamoudi D, Marcadet L, Piette Boulanger A, Yagita H, Bouredji Z, Argaw A, Frenette J (2019) An anti-RANKL treatment reduces muscle inflammation and dysfunction and strengthens bone in dystrophic mice. Hum Mol Genet 28:3101–3112

    Article  CAS  PubMed  Google Scholar 

  115. Xiong J, Le Y, Rao Y, Zhou L, Hu Y, Guo S, Sun Y (2021) RANKL mediates muscle atrophy and dysfunction in a cigarette smoke-induced model of chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 64:617–628

    Article  CAS  PubMed  Google Scholar 

  116. Huang J, Romero-Suarez S, Lara N, Mo C, Kaja S, Brotto L, Dallas SL, Johnson ML, Jähn K, Bonewald LF, Brotto M (2017) Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/β-catenin pathway. JBMR Plus 1:86–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Jürimäe J, Karvelyte V, Remmel L, Tamm AL, Purge P, Gruodyte-Raciene R, Kamandulis S, Maasalu K, Gracia-Marco L, Tillmann V (2021) Serum sclerostin concentration is associated with specific adipose, muscle and bone tissue markers in lean adolescent females with increased physical activity. J Pediatr Endocrinol Metab 34:755–761

    Article  PubMed  Google Scholar 

  118. Kim JA, Roh E, Hong SH, Lee YB, Kim NH, Yoo HJ, Seo JA, Kim NH, Kim SG, Baik SH, Choi KM (2019) Association of serum sclerostin levels with low skeletal muscle mass: the Korean sarcopenic obesity study (KSOS). Bone 128:115053

    Article  CAS  PubMed  Google Scholar 

  119. Armstrong DD, Esser KA (2005) Wnt/beta-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy. Am J Physiol Cell Physiol 289:C853-859

    Article  CAS  PubMed  Google Scholar 

  120. Manolagas SC (2020) Osteocalcin promotes bone mineralization but is not a hormone. PLoS Genet 16:e1008714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Komori T (2020) Functions of osteocalcin in bone, pancreas, testis, and muscle. Int J Mol Sci 21:7513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Karsenty G, Mera P (2018) Molecular bases of the crosstalk between bone and muscle. Bone 115:43–49

    Article  CAS  PubMed  Google Scholar 

  123. Moriishi T, Ozasa R, Ishimoto T, Nakano T, Hasegawa T, Miyazaki T, Liu W, Fukuyama R, Wang Y, Komori H, Qin X, Amizuka N, Komori T (2020) Osteocalcin is necessary for the alignment of apatite crystallites, but not glucose metabolism, testosterone synthesis, or muscle mass. PLoS Genet 16:e1008586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Diegel CR, Hann S, Ayturk UM, Hu JCW, Lim KE, Droscha CJ, Madaj ZB, Foxa GE, Izaguirre I, Transgenics Core VVA, Paracha N, Pidhaynyy B, Dowd TL, Robling AG, Warman ML, Williams BO (2020) An osteocalcin-deficient mouse strain without endocrine abnormalities. PLoS Genet 16:e1008361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mera P, Laue K, Wei J, Berger JM, Karsenty G (2016) Osteocalcin is necessary and sufficient to maintain muscle mass in older mice. Mol Metab 5:1042–1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Mera P, Laue K, Ferron M, Confavreux C, Wei J, Galán-Díez M, Lacampagne A, Mitchell SJ, Mattison JA, Chen Y, Bacchetta J, Szulc P, Kitsis RN, de Cabo R, Friedman RA, Torsitano C, McGraw TE, Puchowicz M, Kurland I, Karsenty G (2016) Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise. Cell Metab 23:1078–1092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lin X, Parker L, McLennan E, Hayes A, McConell G, Brennan-Speranza TC, Levinger I (2019) Undercarboxylated osteocalcin improves insulin-stimulated glucose uptake in muscles of corticosterone-treated mice. J Bone Miner Res 34:1517–1530

    Article  CAS  PubMed  Google Scholar 

  128. Si Y, Kazamel M, Benatar M, Wuu J, Kwon Y, Kwan T, Jiang N, Kentrup D, Faul C, Alesce L, King PH (2021) FGF23, a novel muscle biomarker detected in the early stages of ALS. Sci Rep 11:12062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Fukasawa H, Ishigaki S, Kinoshita-Katahashi N, Niwa H, Yasuda H, Kumagai H, Furuya R (2014) Plasma levels of fibroblast growth factor-23 are associated with muscle mass in haemodialysis patients. Nephrology (Carlton) 19:784–790

    Article  CAS  PubMed  Google Scholar 

  130. Avin KG, Vallejo JA, Chen NX, Wang K, Touchberry CD, Brotto M, Dallas SL, Moe SM, Wacker MJ (2018) Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility. Am J Physiol Endocrinol Metab 315:E594-e604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gladding A, Szymczuk V, Auble BA, Boyce AM (2021) Burosumab treatment for fibrous dysplasia. Bone 150:116004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mo C, Zhao R, Vallejo J, Igwe O, Bonewald L, Wetmore L, Brotto M (2015) Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation. Cell Cycle 14:1507–1516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Palla AR, Ravichandran M, Wang YX, Alexandrova L, Yang AV, Kraft P, Holbrook CA, Schürch CM, Ho ATV, Blau HM (2021) Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science. https://doi.org/10.1126/science.abc8059

    Article  PubMed  Google Scholar 

  134. Klein GL (2022) Transforming growth factor-beta in skeletal muscle wasting. Int J Mol Sci. https://doi.org/10.3390/ijms23031167

    Article  PubMed  PubMed Central  Google Scholar 

  135. Ábrigo J, Campos F, Simon F, Riedel C, Cabrera D, Vilos C, Cabello-Verrugio C (2018) TGF-β requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy. Biol Chem 399:253–264

    Article  PubMed  Google Scholar 

  136. Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J (2004) Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: a key event in muscle fibrogenesis. Am J Pathol 164:1007–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Waning DL, Mohammad KS, Reiken S, Xie W, Andersson DC, John S, Chiechi A, Wright LE, Umanskaya A, Niewolna M, Trivedi T, Charkhzarrin S, Khatiwada P, Wronska A, Haynes A, Benassi MS, Witzmann FA, Zhen G, Wang X, Cao X, Roodman GD, Marks AR, Guise TA (2015) Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat Med 21:1262–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Pin F, Bonetto A, Bonewald LF, Klein GL (2019) Molecular mechanisms responsible for the rescue effects of pamidronate on muscle atrophy in pediatric burn patients. Front Endocrinol (Lausanne) 10:543

    Article  PubMed  Google Scholar 

  139. Regan JN, Waning DL, Guise TA (2016) Skeletal muscle Ca(2+) mishandling: another effect of bone-to-muscle signaling. Semin Cell Dev Biol 49:24–29

    Article  CAS  PubMed  Google Scholar 

  140. Sartori R, Sandri M (2015) BMPs and the muscle-bone connection. Bone 80:37–42

    Article  CAS  PubMed  Google Scholar 

  141. Sartori R, Schirwis E, Blaauw B, Bortolanza S, Zhao J, Enzo E, Stantzou A, Mouisel E, Toniolo L, Ferry A, Stricker S, Goldberg AL, Dupont S, Piccolo S, Amthor H, Sandri M (2013) BMP signaling controls muscle mass. Nat Genet 45:1309–1318

    Article  CAS  PubMed  Google Scholar 

  142. Sartori R, Hagg A, Zampieri S, Armani A, Winbanks CE, Viana LR, Haidar M, Watt KI, Qian H, Pezzini C, Zanganeh P, Turner BJ, Larsson A, Zanchettin G, Pierobon ES, Moletta L, Valmasoni M, Ponzoni A, Attar S, Da Dalt G, Sperti C, Kustermann M, Thomson RE, Larsson L, Loveland KL, Costelli P, Megighian A, Merigliano S, Penna F, Gregorevic P, Sandri M (2021) Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia. Sci Transl Med 13:10

    Article  Google Scholar 

  143. Yoshida T, Delafontaine P (2020) Mechanisms of IGF-1-mediated regulation of skeletal muscle hypertrophy and atrophy. Cells 9:1970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M (2013) Mechanisms regulating skeletal muscle growth and atrophy. Febs j 280:4294–4314

    Article  CAS  PubMed  Google Scholar 

  145. Sullivan BP, Weiss JA, Nie Y, Garner RT, Drohan CJ, Kuang S, Stout J, Gavin TP (2020) Skeletal muscle IGF-1 is lower at rest and after resistance exercise in humans with obesity. Eur J Appl Physiol 120:2835–2846

    Article  CAS  PubMed  Google Scholar 

  146. Bucci L, Yani SL, Fabbri C, Bijlsma AY, Maier AB, Meskers CG, Narici MV, Jones DA, McPhee JS, Seppet E, Gapeyeva H, Pääsuke M, Sipilä S, Kovanen V, Stenroth L, Musarò A, Hogrel JY, Barnouin Y, Butler-Browne G, Capri M, Franceschi C, Salvioli S (2013) Circulating levels of adipokines and IGF-1 are associated with skeletal muscle strength of young and old healthy subjects. Biogerontology 14:261–272

    Article  CAS  PubMed  Google Scholar 

  147. Li B, Feng L, Wu X, Cai M, Yu JJ, Tian Z (2022) Effects of different modes of exercise on skeletal muscle mass and function and IGF-1 signaling during early aging in mice. J Exp Biol. https://doi.org/10.1242/jeb.244650

    Article  PubMed  PubMed Central  Google Scholar 

  148. Lau KH, Baylink DJ, Sheng MH (2015) Osteocyte-derived insulin-like growth factor I is not essential for the bone repletion response in mice. PLoS ONE 10:e0115897

    Article  PubMed  PubMed Central  Google Scholar 

  149. Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, Spiegelman BM (2014) Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513:100–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kir S, Komaba H, Garcia AP, Economopoulos KP, Liu W, Lanske B, Hodin RA, Spiegelman BM (2016) PTH/PTHrP receptor mediates cachexia in models of kidney failure and cancer. Cell Metab 23:315–323

    Article  CAS  PubMed  Google Scholar 

  151. Weber BZC, Agca S, Domaniku A, Bilgic SN, Arabaci DH, Kir S (2022) Inhibition of epidermal growth factor receptor suppresses parathyroid hormone-related protein expression in tumours and ameliorates cancer-associated cachexia. J Cachexia Sarcopenia Muscle 13:1582–1594

    Article  PubMed  PubMed Central  Google Scholar 

  152. Zhong L, Yuan J, Huang L, Li S, Deng L (2020) RANKL is involved in Runx2-triggered hepatic infiltration of macrophages in mice with NAFLD induced by a high-fat diet. Biomed Res Int 2020:6953421

    Article  PubMed  PubMed Central  Google Scholar 

  153. Kim SP, Frey JL, Li Z, Kushwaha P, Zoch ML, Tomlinson RE, Da H, Aja S, Noh HL, Kim JK, Hussain MA, Thorek DLJ, Wolfgang MJ, Riddle RC (2017) Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. Proc Natl Acad Sci U S A 114:E11238–E11247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Oh H, Park SY, Cho W, Abd El-Aty AM, Hacimuftuoglu A, Kwon CH, Jeong JH, Jung TW (2022) Sclerostin aggravates insulin signaling in skeletal muscle and hepatic steatosis via upregulation of ER stress by mTOR-mediated inhibition of autophagy under hyperlipidemic conditions. J Cell Physiol 237:4226–4237

    Article  CAS  PubMed  Google Scholar 

  155. Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G (2012) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. Bone 50:568–575

    Article  CAS  PubMed  Google Scholar 

  156. Zhou B, Li H, Xu L, Zang W, Wu S, Sun H (2013) Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-kappaB signaling pathway. Endocrinology 154:1055–1068

    Article  CAS  PubMed  Google Scholar 

  157. Wang JS, Mazur CM, Wein MN (2021) Sclerostin and osteocalcin: candidate bone-produced hormones. Front Endocrinol (Lausanne) 12:584147

    Article  PubMed  Google Scholar 

  158. Ferron M, Lacombe J (2014) Regulation of energy metabolism by the skeleton: osteocalcin and beyond. Arch Biochem Biophys 561:137–146

    Article  CAS  PubMed  Google Scholar 

  159. Zhang M, Nie X, Yuan Y, Wang Y, Ma X, Yin J, Bao Y (2021) Osteocalcin alleviates nonalcoholic fatty liver disease in mice through GPRC6A. Int J Endocrinol 2021:9178616

    Article  PubMed  PubMed Central  Google Scholar 

  160. Mattinzoli D, Ikehata M, Tsugawa K, Alfieri CM, Dongiovanni P, Trombetta E, Valenti L, Puliti A, Lazzari L, Messa P (2018) FGF23 and Fetuin-A interaction in the liver and in the circulation. Int J Biol Sci 14:586–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, Czaja MJ, Bartz R, Abraham R, Di Marco GS, Brand M, Wolf M, Faul C (2016) Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 90:985–996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Mattinzoli D, Li M, Castellano G, Ikehata M, Armelloni S, Elli FM, Molinari P, Tsugawa K, Alfieri CM, Messa P (2022) Fibroblast growth factor 23 level modulates the hepatocyte’s alpha-2-HS-glycoprotein transcription through the inflammatory pathway TNFalpha/NFkappaB. Front Med (Lausanne) 9:1038638

    Article  PubMed  Google Scholar 

  163. Cao Y, Mai W, Li R, Deng S, Li L, Zhou Y, Qin Q, Zhang Y, Zhou X, Han M, Liang P, Yan Y, Hao Y, Xie W, Yan J, Zhu L (2022) Macrophages evoke autophagy of hepatic stellate cells to promote liver fibrosis in NAFLD mice via the PGE2/EP4 pathway. Cell Mol Life Sci 79:303

    Article  CAS  PubMed  Google Scholar 

  164. Rincon-Sanchez AR, Covarrubias A, Rivas-Estilla AM, Pedraza-Chaverri J, Cruz C, Islas-Carbajal MC, Panduro A, Estanes A, Armendariz-Borunda J (2005) PGE2 alleviates kidney and liver damage, decreases plasma renin activity and acute phase response in cirrhotic rats with acute liver damage. Exp Toxicol Pathol 56:291–303

    Article  CAS  PubMed  Google Scholar 

  165. Zhong D, Cai J, Hu C, Chen J, Zhang R, Fan C, Li S, Zhang H, Xu Z, Jia Z, Guo D, Sun Y (2022) Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme. Hepatology. https://doi.org/10.1002/hep.32671

    Article  PubMed  Google Scholar 

  166. Bi J, Ge S (2014) Potential roles of BMP9 in liver fibrosis. Int J Mol Sci 15:20656–20667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Wang Y, Ma C, Sun T, Ren L (2020) Potential roles of bone morphogenetic protein-9 in glucose and lipid homeostasis. J Physiol Biochem 76:503–512

    Article  PubMed  Google Scholar 

  168. Cui B, Yang L, Zhao Y, Lu X, Song M, Liu C, Yang C (2022) HOXA13 promotes liver regeneration through regulation of BMP-7. Biochem Biophys Res Commun 623:23–31

    Article  CAS  PubMed  Google Scholar 

  169. Osganian SA, Subudhi S, Masia R, Drescher HK, Bartsch LM, Chicote ML, Chung RT, Gee DW, Witkowski ER, Bredella MA, Lauer GM, Corey KE, Dichtel LE (2022) Expression of IGF-1 receptor and GH receptor in hepatic tissue of patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Growth Horm IGF Res 65:101482

    Article  CAS  PubMed  Google Scholar 

  170. Caro JF, Poulos J, Ittoop O, Pories WJ, Flickinger EG, Sinha MK (1988) Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. J Clin Invest 81:976–981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Stefano JT, Correa-Giannella ML, Ribeiro CM, Alves VA, Massarollo PC, Machado MC, Giannella-Neto D (2006) Increased hepatic expression of insulin-like growth factor-I receptor in chronic hepatitis C. World J Gastroenterol 12:3821–3828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Dichtel LE, Cordoba-Chacon J, Kineman RD (2022) Growth hormone and insulin-like growth factor 1 regulation of nonalcoholic fatty liver disease. J Clin Endocrinol Metab 107:1812–1824

    Article  PubMed  PubMed Central  Google Scholar 

  173. Shi M, Zhou Z, Zhou Z, Shen L, Shen J, Zhou G, Zhu R (2022) Identification of key genes and infiltrating immune cells among acetaminophen-induced acute liver failure and HBV-associated acute liver failure. Ann Transl Med 10:775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Liang FF, Liu CP, Li LX, Xue MM, Xie F, Guo Y, Bai L (2013) Activated effects of parathyroid hormone-related protein on human hepatic stellate cells. PLoS ONE 8:e76517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Funk JL, Moser AH, Grunfeld C, Feingold KR (1997) Parathyroid hormone-related protein is induced in the adult liver during endotoxemia and stimulates the hepatic acute phase response. Endocrinology 138:2665–2673

    Article  CAS  PubMed  Google Scholar 

  176. Qin B, Diao N, Bai L (2021) Parathyroid hormone-related protein aggravates nonalcoholic fatty liver disease induced by methionine choline-deficient diet in mice. Nan Fang Yi Ke Da Xue Xue Bao 41:1037–1043

    CAS  PubMed  Google Scholar 

  177. Qin B, Qincao L, He S, Liao Y, Shi J, Xie F, Diao N, Bai L (2022) Parathyroid hormone-related protein prevents high-fat-diet-induced obesity, hepatic steatosis and insulin resistance in mice. Endocr J 69:55–65

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA

    Anika Shimonty, Lynda F. Bonewald & Joshua R. Huot

  2. Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA

    Anika Shimonty, Lynda F. Bonewald & Joshua R. Huot

  3. Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Lynda F. Bonewald & Joshua R. Huot

  4. Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

    Lynda F. Bonewald

  5. Department of Kinesiology, School of Health and Human Sciences, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA

    Joshua R. Huot

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AS, LFB, and JRH conceived the contents of the review; AS and JRH wrote the review; AS, LFB, and JRH edited the review.

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Shimonty, A., Bonewald, L.F. & Huot, J.R. Metabolic Health and Disease: A Role of Osteokines?. Calcif Tissue Int 113, 21–38 (2023). https://doi.org/10.1007/s00223-023-01093-0

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