Allogeneic yet major histocompatibility complex-matched bone marrow transplantation in mice results in an impairment of osteoblasts and a significantly reduced trabecular bone

Abstract

Secondary osteopenia following allogeneic bone marrow or stem cell transplantation (BMT or HSCT) is a significant source of morbidity in patients. It is believed to be caused by a number of factors related to the myeloablative conditioning and subsequent therapy regimen. We here aimed to investigate whether the allogeneic bone marrow by itself directly impacts on the bone mass of the patient. We thus performed syn- and allogeneic BMT between two inbred mouse strains, which share an identical major histocompatibility complex background yet differ in their bone phenotypes. BMT was well tolerated, yielded survival rates of 97% and allowed for a regular physiological development. However, allogeneic BMT led to a significant reduction of trabecular bone mass that was independent of strain, sex, immunosuppressive medication, complications resulting from graft versus host disease, underlying bone phenotype and numbers of osteoclasts. Instead, reduced trabecular bone mass correlated with reduced plasma levels of amino-terminal propeptide of type I collagen. Our results suggest that osteopenia following allogeneic BMT is significantly influenced by an impaired osteoblast activity that may stem from a lack of communication between the resident osteoblasts and an allogeneic bone marrow-derived cell type. Elucidating this incompatibility will open new approaches for the therapy of secondary osteopenia.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Cupit MC, Duncan C, Savani BN, Hashmi SK (2016) Childhood to adult transition and long-term follow-up after blood and marrow transplantation. Bone Marrow Transplant 51:176–181

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    McClune BL, Majhail NS (2013) Osteoporosis after stem cell transplantation. Curr Osteoporos Rep 11:305–310

    Article  PubMed  Google Scholar 

  3. 3.

    Pirsl F, Curtis LM, Steinberg SM, Tella SH, Katić M, Dobbin M, Hsu J, Hakim FT, Mays JW, Im AP, Pulanić D, Mitchell SA, Baruffaldi J, Masuch L, Halverson DC, Gress RE, Barsony J, Pavletic SZ (2016) Characterization and risk factor analysis of osteoporosis in a large cohort of patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant 22:1517–1524

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373:1550–1561

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Ebeling PR, Thomas DM, Erbas B, Hopper JL, Szer J, Grigg AP (1999) Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation. J Bone Miner Res 14:342–350

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Serio B, Pezzullo L, Fontana R, Annunziata S, Rosamilio R, Sessa M, Giudice V, Ferrara I, Rocco M, De Rosa G, Ricci P, Tauchmanovà L, Montuori N, Selleri C (2013) Accelerated bone mass senescence after hematopoietic stem cell transplantation. Transl Med UniSa 5:7–13

    PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Weitzmann MN (2013) The role of inflammatory cytokines, the RANKL/OPG axis, and the immunoskeletal interface in physiological bone turnover and osteoporosis. Scientifica (Cairo) 2013:125705

    Google Scholar 

  8. 8.

    Sims NA, Martin TJ (2014) Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep 3:481

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Johnson RW, McGregor NE, Brennan HJ, Crimeen-Irwin B, Poulton IJ, Martin TJ, Sims NA (2015) Glycoprotein130 (Gp130)/interleukin-6 (IL-6) signalling in osteoclasts promotes bone formation in periosteal and trabecular bone. Bone 81:343–351

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Pasold J, Engelmann R, Keller J, Joost S, Marshall RP, Frerich B, Müller-Hilke B (2013) High bone mass in the STR/ort mouse results from increased bone formation and impaired bone resorption and is associated with extramedullary hematopoiesis. J Bone Miner Metab 31:71–81

    Article  PubMed  Google Scholar 

  11. 11.

    Ferguson VL, Ayers RA, Bateman TA, Simske SJ (2003) Bone development and age-related bone loss in male C57BL/6J mice. Bone 33:387–398

    Article  PubMed  Google Scholar 

  12. 12.

    Lee S, Iwai H, Sugiura K, Takeuchi K, Kushida T, Tomoda K, Inaba M, Yamashita T, Ikehara S (2000) Prevention of autoimmune hearing loss in MRL/lpr mice by bone marrow transplantation. Bone Marrow Transplant 26:887–892

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Jaeger K, Selent C, Jaehme W, Mahr S, Goebel U, Ibrahim S, Vollmar B, Mueller-Hilke B (2008) The genetics of osteoarthritis in STR/ort mice. Osteoarthr Cartil 16:607–614

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Colovai AI, Giatzikis C, Ho EK, Farooqi M, Suciu-Foca N, Cattoretti G, Orazi A (2004) Flow cytometric analysis of normal and reactive spleen. Mod Pathol 17:918–927

    Article  PubMed  Google Scholar 

  15. 15.

    Blumer MJ, Hausott B, Schwarzer C, Hayman AR, Stempel J, Fritsch H (2012) Role of tartrate-resistant acid phosphatase (TRAP) in long bone development. Mech Dev 129:162–176

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Aoki H, Hara A, Motohashi T, Kunisada T (2011) Protective effect of Kit signaling for melanocyte stem cells against radiation-induced genotoxic stress. J Investig Dermatol 131:1906–1915

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Uchida K, Naruse K, Satoh M, Onuma K, Ueno M, Takano S, Urabe K, Takaso M (2013) Increase of circulating CD11b(+)Gr1(+) cells and recruitment into the synovium in osteoarthritic mice with hyperlipidemia. Exp Anim 62:255–265

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    He J, Qiu W, Zhang Z, Wang Z, Zhang X, He Y (2011) Effects of irradiation on growth and differentiation-related gene expression in osteoblasts. J Craniofac Surg 22:1635–1640

    Article  PubMed  Google Scholar 

  19. 19.

    Lee WY, Baek KH, Rhee EJ, Tae HJ, Oh KW, Kang MI, Lee KW, Kim SW, Kim CC, Oh ES (2004) Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation. Bone Marrow Transplant 34:89–94

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT (1999) Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 265:144–150

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Terreni A, Pezzati P (2012) Biochemical markers in the follow-up of the osteoporotic patients. Clin Cases Miner Bone Metab 9:80–84

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Koivula MK, Risteli L, Risteli J (2012) Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum. Clin Biochem 45:920–927

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Florencio-Silva R, Sasso GR, Sasso-Cerri E, Simoes MJ, Cerri PS (2015) Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int 2015:421746

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Lee WY, Cho SW, Oh ES, Oh KW, Lee JM, Yoon KH, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim CC (2002) The effect of bone marrow transplantation on the osteoblastic differentiation of human bone marrow stromal cells. J Clin Endocrinol Metab 87:329–335

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T, Matsuo K (2006) Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab 4:111–121

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Walker EC, McGregor NE, Poulton IJ, Pompolo S, Allan EH, Quinn JM, Gillespie MT, Martin TJ, Sims NA (2008) Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J Bone Miner Res 23:2025–2032

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Ryu J, Kim HJ, Chang EJ, Huang H, Banno Y, Kim HH (2006) Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. EMBO J 25:5840–5851

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 29.

    Keller J, Catala-Lehnen P, Huebner AK, Jeschke A, Heckt T et al (2014) Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts. Nat Commun 21:5215

    Article  CAS  Google Scholar 

  30. 30.

    Takeshita S, Fumoto T, Matsuoka K, Park KA, Aburatani H, Kato S, Ito M, Ikeda K (2013) Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J Clin Investig 123:3914–3924

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Hautmann AH, Elad S, Lawitschka A, Greinix H, Bertz H, Halter J, Faraci M, Hofbauer LC, Lee S, Wolff D, Holler E (2011) Metabolic bone diseases in patients after allogeneic hematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease. Transpl Int 24:867–879

    Article  PubMed  Google Scholar 

  32. 32.

    Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, Maylin ER, Ripoll VM, Hume DA, Pettit AR (2008) Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol 181:1232–1244

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Pettit AR, Chang MK, Hume DA, Raggatt LJ (2008) Osteal macrophages: a new twist on coupling during bone dynamics. Bone 43:976–982

    Article  PubMed  Google Scholar 

  34. 34.

    Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, Poulton IJ, van Rooijen N, Alexander KA, Raggatt LJ, Lévesque JP (2010) Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116:4815–4828

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Winkler IG, Pettit AR, Raggatt LJ, Jacobsen RN, Forristal CE, Barbier V, Nowlan B, Cisterne A, Bendall LJ, Sims NA, Lévesque JP (2012) Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation. Leukemia 26:1594–1601

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Heino TJ, Hentunen TA, Vaananen HK (2002) Osteocytes inhibit osteoclastic bone resorption through transforming growth factor-beta: enhancement by estrogen. J Cell Biochem 85:185–197

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Aguirre JI, Plotkin LI, Stewart SA, Weinstein RS, Parfitt AM, Manolagas SC, Bellido T (2006) Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J Bone Miner Res 21:605–615

    Article  PubMed  Google Scholar 

  38. 38.

    Heino TJ, Kurata K, Higaki H, Vaananen HK (2009) Evidence for the role of osteocytes in the initiation of targeted remodeling. Technol Health Care 17:49–56

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Ilona Klamfuß and Karin Gerber (Institute of Experimental Surgery) for taking excellent care of the mice. This study was funded by an intramural grant (FORUN_Os). AO was funded by a fellowship from the federal state of Mecklenburg-Vorpommern and Rostock University Medical Center.

Author information

Affiliations

Authors

Contributions

AO and BMH conceived and designed the work that led to the submission, AO acquired the data, AO, RE and BMH played important roles in interpreting the results, AO and BMH drafted the manuscript, AO, RE and BMH revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Brigitte Müller-Hilke.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Osterberg, A., Engelmann, R. & Müller-Hilke, B. Allogeneic yet major histocompatibility complex-matched bone marrow transplantation in mice results in an impairment of osteoblasts and a significantly reduced trabecular bone. J Bone Miner Metab 36, 420–430 (2018). https://doi.org/10.1007/s00774-017-0859-y

Download citation

Keywords

  • Allogeneic and syngeneic bone marrow transfer
  • Osteoporosis
  • µCT
  • Bone remodeling