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.
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References
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
McClune BL, Majhail NS (2013) Osteoporosis after stem cell transplantation. Curr Osteoporos Rep 11:305–310
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
Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373:1550–1561
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Terreni A, Pezzati P (2012) Biochemical markers in the follow-up of the osteoporotic patients. Clin Cases Miner Bone Metab 9:80–84
Koivula MK, Risteli L, Risteli J (2012) Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum. Clin Biochem 45:920–927
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
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
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
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
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
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
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
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
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
Pettit AR, Chang MK, Hume DA, Raggatt LJ (2008) Osteal macrophages: a new twist on coupling during bone dynamics. Bone 43:976–982
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
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
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
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
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
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.
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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.
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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
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DOI: https://doi.org/10.1007/s00774-017-0859-y