Skip to main content

Advertisement

SpringerLink
Log in

Nmp4, a Regulator of Induced Osteoanabolism, Also Influences Insulin Secretion and Sensitivity

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

A bidirectional and complex relationship exists between bone and glycemia. Persons with type 2 diabetes (T2D) are at risk for bone loss and fracture, however, heightened osteoanabolism may ameliorate T2D-induced deficits in glycemia as bone-forming osteoblasts contribute to energy metabolism via increased glucose uptake and cellular glycolysis. Mice globally lacking nuclear matrix protein 4 (Nmp4), a transcription factor expressed in all tissues and conserved between humans and rodents, are healthy and exhibit enhanced bone formation in response to anabolic osteoporosis therapies. To test whether loss of Nmp4 similarly impacted bone deficits caused by diet-induced obesity, male wild-type and Nmp4−/− mice (8 weeks) were fed either low-fat diet or high-fat diet (HFD) for 12 weeks. Endpoint parameters included bone architecture, structural and estimated tissue-level mechanical properties, body weight/composition, glucose-stimulated insulin secretion, glucose tolerance, insulin tolerance, and metabolic cage analysis. HFD diminished bone architecture and ultimate force and stiffness equally in both genotypes. Unexpectedly, the Nmp4−/− mice exhibited deficits in pancreatic β-cell function and were modestly glucose intolerant under normal diet conditions. Despite the β-cell deficits, the Nmp4−/− mice were less sensitive to HFD-induced weight gain, increases in % fat mass, and decreases in glucose tolerance and insulin sensitivity. We conclude that Nmp4 supports pancreatic β-cell function but suppresses peripheral glucose utilization, perhaps contributing to its suppression of induced skeletal anabolism. Selective disruption of Nmp4 in peripheral tissues may provide a strategy for improving both induced osteoanabolism and energy metabolism in comorbid patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Melton LJ 3rd, Leibson CL, Achenbach SJ, Therneau TM, Khosla S (2008) Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res 23:1334–1342

    PubMed  PubMed Central  Google Scholar 

  2. Bonds DE, Larson JC, Schwartz AV et al (2006) Risk of fracture in women with type 2 diabetes: the Women’s Health Initiative Observational Study. J Clin Endocrinol Metab 91:3404–3410

    CAS  PubMed  Google Scholar 

  3. Tebe C, Martinez-Laguna D, Carbonell-Abella C et al (2019) The association between type 2 diabetes mellitus, hip fracture, and post-hip fracture mortality: a multi-state cohort analysis. Osteoporos Int 30:2407–2415

    CAS  PubMed  Google Scholar 

  4. Yilmaz V, Umay E, Gundogdu I, Tezel N (2018) Effect of type 2 diabetes mellitus on treatment outcomes of patients with postmenopausal osteoporosis: a retrospective study. J Diabetes Metab Disord 17:181–187

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Hamann C, Goettsch C, Mettelsiefen J et al (2011) Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function. Am J Physiol Endocrinol Metab 301:E1220–E1228

    CAS  PubMed  Google Scholar 

  6. Kawashima Y, Fritton JC, Yakar S et al (2009) Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis. Bone 44:648–655

    PubMed  Google Scholar 

  7. Weinberg E, Maymon T, Weinreb M (2014) AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFalpha production and oxidative stress. J Mol Endocrinol 52:67–76

    CAS  PubMed  Google Scholar 

  8. Villarino ME, Sanchez LM, Bozal CB, Ubios AM (2006) Influence of short-term diabetes on osteocytic lacunae of alveolar bone. A histomorphometric study. Acta Odontol Latinoam: AOL 19:23–28

    PubMed  Google Scholar 

  9. Ionova-Martin SS, Do SH, Barth HD et al (2010) Reduced size-independent mechanical properties of cortical bone in high-fat diet-induced obesity. Bone 46:217–225

    CAS  PubMed  Google Scholar 

  10. Ionova-Martin SS, Wade JM, Tang S et al (2011) Changes in cortical bone response to high-fat diet from adolescence to adulthood in mice. Osteoporos Int 22:2283–2293

    CAS  PubMed  Google Scholar 

  11. Karim L, Bouxsein ML (2016) Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties. Bone 82:21–27

    CAS  PubMed  Google Scholar 

  12. Shi J, Fan J, Su Q, Yang Z (2019) Cytokines and abnormal glucose and lipid metabolism. Front Endocrinol 10:703

    Google Scholar 

  13. Faienza MF, Luce V, Ventura A et al (2015) Skeleton and glucose metabolism: a bone-pancreas loop. Int J Endocrinol. https://doi.org/10.1155/2015/758148

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dirckx N, Tower RJ, Mercken EM et al (2018) Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism. J Clin Investig 128:1087–1105

    PubMed  PubMed Central  Google Scholar 

  15. Guntur AR, Gerencser AA, Le PT et al (2018) Osteoblast-like MC3T3-E1 cells prefer glycolysis for ATP production but adipocyte-like 3T3-L1 cells prefer oxidative phosphorylation. J Bone Miner Res. https://doi.org/10.1002/jbmr.3390

    Article  PubMed  Google Scholar 

  16. Karner CM, Long F (2017) Glucose metabolism in bone. Bone. https://doi.org/10.1016/j.bone.2017.08.008

    Article  PubMed  PubMed Central  Google Scholar 

  17. Clemens TL, Karsenty G (2011) The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res 26:677–680

    CAS  PubMed  Google Scholar 

  18. Ferron M, Wei J, Yoshizawa T et al (2010) Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 142:296–308

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Fulzele K, Riddle RC, DiGirolamo DJ et al (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tangseefa P, Martin SK, Fitter S, Baldock PA, Proud CG, Zannettino ACW (2018) Osteocalcin-dependent regulation of glucose metabolism and fertility: skeletal implications for the development of insulin resistance. J Cell Physiol 233:3769–3783

    CAS  PubMed  Google Scholar 

  21. Lee NK, Sowa H, Hinoi E et al (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Diegel CR, Hann S, Ayturk UM et al (2020) An osteocalcin-deficient mouse strain without endocrine abnormalities. PLoS Genet 16:e1008361

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Karsenty G (2020) The facts of the matter: what is a hormone? PLoS Genet 16:e1008938

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang X, Zhang G, Qi F et al (2018) Enhanced bone regeneration using an insulin-loaded nano-hydroxyapatite/collagen/PLGA composite scaffold. Int J Nanomed 13:117–127

    Google Scholar 

  25. Childress P, Philip BK, Robling AG et al (2011) Nmp4/CIZ suppresses the response of bone to anabolic parathyroid hormone by regulating both osteoblasts and osteoclasts. Calcif Tissue Int 89:74–89

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Childress P, Stayrook KR, Alvarez MB et al (2015) Genome-wide mapping and interrogation of the Nmp4 antianabolic bone axis. Mol Endocrinol 29:1269–1285

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Shao Y, Hernandez-Buquer S, Childress P et al (2017) Improving combination osteoporosis therapy in a preclinical model of heightened osteoanabolism. Endocrinology 158:2722–2740

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shao Y, Wichern E, Childress PJ et al (2019) Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality. Am J Physiol Endocrinol Metab 316:E749–E772

    PubMed  PubMed Central  Google Scholar 

  29. Thunyakitpisal P, Alvarez M, Tokunaga K et al (2001) Cloning and functional analysis of a family of nuclear matrix transcription factors (NP/NMP4) that regulate type I collagen expression in osteoblasts. J Bone Miner Res 16:10–23

    CAS  PubMed  Google Scholar 

  30. Robling AG, Childress P, Yu J et al (2009) Nmp4/CIZ suppresses parathyroid hormone-induced increases in trabecular bone. J Cell Physiol 219:734–743

    CAS  PubMed  PubMed Central  Google Scholar 

  31. He Y, Childress P, Hood M Jr et al (2013) Nmp4/CIZ suppresses the parathyroid hormone anabolic window by restricting mesenchymal stem cell and osteoprogenitor frequency. Stem Cells Dev 22:492–500

    CAS  PubMed  Google Scholar 

  32. Lee SY, Long F (2018) Notch signaling suppresses glucose metabolism in mesenchymal progenitors to restrict osteoblast differentiation. J Clin Investig 128:5573–5586

    PubMed  PubMed Central  Google Scholar 

  33. Lacombe J, Al Rifai O, Loter L et al (2020) Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and beta-cell function. Am J Physiol Endocrinol Metab 318:E381–E391

    PubMed  PubMed Central  Google Scholar 

  34. Le Doan V, Marcil V (2017) Osteocalcin and glucose metabolism: assessment of human studies. Med Sci (Paris) 33:417–422

    Google Scholar 

  35. Young SK, Shao Y, Bidwell JP, Wek RC (2016) Nuclear matrix protein 4 is a novel regulator of ribosome biogenesis and controls the unfolded protein response via repression of Gadd34 expression. J Biol Chem. https://doi.org/10.1074/jbc.M116.729830

    Article  PubMed  PubMed Central  Google Scholar 

  36. Powell KM, Brown AP, Skaggs CG et al (2020) 6’-Methoxy raloxifene-analog enhances mouse bone properties with reduced estrogen receptor binding. Bone Rep 12:100246

    PubMed  PubMed Central  Google Scholar 

  37. Bart ZR, Hammond MA, Wallace JM (2014) Multi-scale analysis of bone chemistry, morphology and mechanics in the oim model of osteogenesis imperfecta. Connect Tissue Res 55(Suppl 1):4–8

    CAS  PubMed  Google Scholar 

  38. Sims EK, Hatanaka M, Morris DL et al (2013) Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains. Am J Physiol Endocrinol Metab 305:E1495–E1511

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Evans-Molina C, Robbins RD, Kono T et al (2009) Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure. Mol Cell Biol 29:2053–2067

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Stull ND, Breite A, McCarthy R, Tersey SA, Mirmira RG (2012) Mouse islet of Langerhans isolation using a combination of purified collagenase and neutral protease. J Vis Exp: JoVE. https://doi.org/10.3791/4137

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tong X, Kono T, Anderson-Baucum EK et al (2016) SERCA2 deficiency impairs pancreatic beta-cell function in response to diet-induced obesity. Diabetes 65:3039–3052

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yang S, Adaway M, Du J et al (2020) NMP4 regulates the innate immune response to influenza A virus infection. Mucosal Immunol. https://doi.org/10.1038/s41385-020-0280-z

    Article  PubMed  PubMed Central  Google Scholar 

  43. Nakamoto T, Izu Y, Kawasaki M et al (2016) Mice deficient in CIZ/NMP4 develop an attenuated form of K/BxN-serum induced arthritis. J Cell Biochem 117:970–977

    CAS  PubMed  Google Scholar 

  44. Zoch ML, Abou DS, Clemens TL, Thorek DL, Riddle RC (2016) In vivo radiometric analysis of glucose uptake and distribution in mouse bone. Bone Res 4:16004

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Wei J, Shimazu J, Makinistoglu MP et al (2015) Glucose uptake and Runx2 synergize to orchestrate osteoblast differentiation and bone formation. Cell 161:1576–1591

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang YY, Zhou YM, Xu JZ et al (2021) Lgr4 promotes aerobic glycolysis and differentiation in osteoblasts via the canonical Wnt/β-catenin pathway. J Bone Miner Res. https://doi.org/10.1002/jbmr.4321

    Article  PubMed  Google Scholar 

  47. Regan JN, Lim J, Shi Y et al (2014) Up-regulation of glycolytic metabolism is required for HIF1alpha-driven bone formation. Proc Natl Acad Sci USA 111:8673–8678

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Esen E, Lee SY, Wice BM, Long F (2015) PTH promotes bone anabolism by stimulating aerobic glycolysis via IGF signaling. J Bone Miner Res 30:1959–1968

    CAS  PubMed  Google Scholar 

  49. Atkinson E, Adaway M, Korff C et al (2020) Conditional loss of Nmp4 in mesenchymal stem progenitor cells enhances PTH-induced bone formation. J Bone Miner Res 35:136

    Google Scholar 

  50. Tencerova M, Figeac F, Ditzel N, Taipaleenmäki H, Nielsen TK, Kassem M (2018) High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice. J Bone Miner Res 33:1154–1165

    CAS  PubMed  Google Scholar 

  51. Ross DS, Yeh TH, King S et al (2021) Distinct effects of a high fat diet on bone in skeletally mature and developing male C57BL/6J mice. Nutrients. https://doi.org/10.3390/nu13051666

    Article  PubMed  PubMed Central  Google Scholar 

  52. Schwartz AV, Pavo I, Alam J et al (2016) Teriparatide in patients with osteoporosis and type 2 diabetes. Bone 91:152–158

    CAS  PubMed  Google Scholar 

  53. Dhaliwal R, Hans D, Hattersley G et al (2020) Abaloparatide in postmenopausal women with osteoporosis and type 2 diabetes: a post hoc analysis of the ACTIVE study. JBMR Plus 4:e10346

    PubMed  PubMed Central  Google Scholar 

  54. Carrat GR, Haythorne E, Tomas A et al (2020) The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis. Mol Metab 40:101015

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Wijesekara N, Dai FF, Hardy AB et al (2010) Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53:1656–1668

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Nicolson TJ, Bellomo EA, Wijesekara N et al (2009) Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58:2070–2083

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health Grants 1R01 AR073739 to J.P.B. and R01 DK093954 and VA Merit Award I01BX001733 (to C.E-M.). The authors would also like to thank The Center for Diabetes & Metabolic Diseases Islet & Physiology Core (P30DK097512) and for performing metabolic assays, islet isolations, and body composition analysis.

Author information

Author notes

  1. Sarah A. Tersey

    Present address: Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA

Authors and Affiliations

  1. Department of Anatomy, Cell Biology, & Physiology (ACBP), Indiana University School of Medicine (IUSM), Indianapolis, IN, 46202, USA

    Joseph Bidwell, Michele Adaway, Angela Klunk, Emily G. Atkinson & Alexander G. Robling

  2. Indiana Center for Musculoskeletal Health, IUSM, Indianapolis, USA

    Joseph Bidwell, Alexander G. Robling & Joseph M. Wallace

  3. Department of Pediatrics, Indiana University School of Medicine (IUSM), Indianapolis, IN, 46202, USA

    Sarah A. Tersey, Robert N. Bone & Carmella Evans-Molina

  4. Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis (IUPUI), Indianapolis, IN, 46202, USA

    Amy Creecy & Joseph M. Wallace

  5. Department of Biochemistry & Molecular Biology, IUSM, Indianapolis, USA

    Ronald C. Wek

  6. Center for Diabetes and Metabolic Disease and the Wells Center for Pediatric Research, IUSM, Indianapolis, IN, 46202, USA

    Robert N. Bone & Carmella Evans-Molina

  7. Richard L. Roudebush VA Medical Center, Indianapolis, USA

    Carmella Evans-Molina

Authors
  1. Joseph Bidwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah A. Tersey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michele Adaway
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert N. Bone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amy Creecy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angela Klunk
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emily G. Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ronald C. Wek
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alexander G. Robling
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joseph M. Wallace
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carmella Evans-Molina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Joseph Bidwell, Joseph M. Wallace or Carmella Evans-Molina.

Ethics declarations

Conflict of interest

Joseph Bidwell, Sarah A. Tersey, Michele Adaway, Robert N. Bone, Amy Creecy, Angela Klunk, Emily G. Atkinson, Ronald C. Wek, Alexander G. Robling, Joseph M. Wallace,and Carmella Evans-Molina have no conflicts of interest to declare that are relevant to the content of this article.

Human and Animal Rights

The Indiana University Institutional Animal Care and Use Committee approved all experimental procedures described in this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bidwell, J., Tersey, S.A., Adaway, M. et al. Nmp4, a Regulator of Induced Osteoanabolism, Also Influences Insulin Secretion and Sensitivity. Calcif Tissue Int 110, 244–259 (2022). https://doi.org/10.1007/s00223-021-00903-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-021-00903-7

Keywords

Search

Navigation