Effects of coagulation factors on bone cells and consequences of their absence in haemophilia a patients.
Bone diseases
Coagulation factors
Haemophilia A
Inherited coagulation disorders
Rare disease
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
23 10 2024
23 10 2024
Historique:
received:
05
07
2024
accepted:
08
10
2024
medline:
24
10
2024
pubmed:
24
10
2024
entrez:
24
10
2024
Statut:
epublish
Résumé
Haemophilia is associated with reduced bone mass and mineral density. Due to the rarity of the disease and the heterogeneity among the studies, the pathogenesis of bone loss is still under investigation. We studied the effects of coagulation factors on bone cells and characterized in a pilot study the osteoclastogenic potential of patients' osteoclast precursors. To evaluate the effect of coagulation factors on osteoclasts, we treated Healthy Donor-Peripheral Blood Mononuclear Cells (HD-PBMC) with Factor VIII (FVIII), von Willebrand Factor (VWF), FVIII/VWF complex, activated Factor IX (FIXa), activated Factor X (FXa) and Thrombin (THB). FVIII, VWF, FVIII/VWF, FXa and THB treatments reduced osteoclast differentiation of HD-PBMC and VWF affected also bone resorption. Interestingly, PBMC isolated from patients with moderate/severe haemophilia showed an increased osteoclastogenic potential due to the alteration of osteoclast precursors. Moreover, increased expression of genes involved in osteoclast differentiation/activity was revealed in osteoclasts of an adult patient with moderate haemophilia. Control osteoblasts treated with the coagulation factors showed that FVIII and VWF reduced ALP positivity; the opposite effect was observed following THB treatment. Moreover, FVIII, VWF and FVIII/VWF reduced mineralization ability. These results could be important to understand how coagulation factors deficiency influences bone remodeling activity in haemophilia.
Identifiants
pubmed: 39443571
doi: 10.1038/s41598-024-75747-w
pii: 10.1038/s41598-024-75747-w
doi:
Substances chimiques
Blood Coagulation Factors
0
Factor VIII
9001-27-8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25001Subventions
Organisme : Ministero dell'Università e della Ricerca
ID : 5x1000-2023
Organisme : Fondazione Umberto Veronesi
ID : 2023
Organisme : Italian Musculoskeletal Apparatus Network RAMS
ID : RAMS
Organisme : Italian Ministry of Health
ID : Current Research funds-2023
Informations de copyright
© 2024. The Author(s).
Références
Escobar, M., Sallah, S. & Hemophilia A and hemophilia B: focus on arthropathy and variables affecting bleeding severity and prophylaxis. J. Thromb. Haemost. 11, 1449–1453. https://doi.org/10.1111/jth.12317 (2013).
doi: 10.1111/jth.12317
pubmed: 23763284
Rodriguez-Merchan, E. C. et al. Joint protection in haemophilia. Haemophilia. 17 (Suppl 2), 1–23. https://doi.org/10.1111/j.1365-2516.2011.02615.x (2011).
doi: 10.1111/j.1365-2516.2011.02615.x
pubmed: 21819491
Stephensen, D. & Rodriguez-Merchan, E. C. Orthopaedic co-morbidities in the elderly haemophilia population: a review. Haemophilia. 19, 166–173. https://doi.org/10.1111/hae.12006 (2013).
doi: 10.1111/hae.12006
pubmed: 22970726
Rodriguez-Merchan, E. C. Hemophilic arthropathy: a teaching approach devoted to hemophilia treaters in under-development countries. Expert Rev. Hematol. 14, 887–896. https://doi.org/10.1080/17474086.2021.1977118 (2021).
doi: 10.1080/17474086.2021.1977118
pubmed: 34482789
Samuelson Bannow, B. et al. Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Rev. 35, 43–50. https://doi.org/10.1016/j.blre.2019.03.002 (2019). Factor VIII.
doi: 10.1016/j.blre.2019.03.002
pubmed: 30922616
Rodriguez-Merchan, E. C. Management of the orthopaedic complications of haemophilia. J. Bone Joint Surg. Br. 80, 191–196 (1998).
doi: 10.1302/0301-620X.80B2.0800191
pubmed: 9546442
Gay, N. D. et al. Increased fracture rates in people with haemophilia: a 10-year single institution retrospective analysis. Br. J. Haematol. 170, 584–586. https://doi.org/10.1111/bjh.13312 (2015).
doi: 10.1111/bjh.13312
pubmed: 25659575
Iorio, A., Fabbriciani, G., Marcucci, M., Brozzetti, M. & Filipponi, P. Bone mineral density in haemophilia patients. A meta-analysis. Thromb. Haemost. 103, 596–603. https://doi.org/10.1160/TH09-09-0629 (2010).
doi: 10.1160/TH09-09-0629
pubmed: 20076854
Kempton, C. L., Antoniucci, D. M. & Rodriguez-Merchan, E. C. Bone health in persons with haemophilia. Haemophilia. 21, 568–577. https://doi.org/10.1111/hae.12736 (2015).
doi: 10.1111/hae.12736
pubmed: 26172840
Anagnostis, P. et al. Reduced bone mineral density in patients with haemophilia A and B in Northern Greece. Thromb. Haemost. 107, 545–551. https://doi.org/10.1160/TH11-08-05563 (2012).
doi: 10.1160/TH11-08-05563
pubmed: 22318743
Kempton, C. L. et al. Bone density in haemophilia: a single institutional cross-sectional study. Haemophilia. 20, 121–128. https://doi.org/10.1111/hae.12240 (2014).
doi: 10.1111/hae.12240
pubmed: 23902277
Gallacher, S. J. et al. Association of severe haemophilia A with osteoporosis: a densitometric and biochemical study. Q. J. Med. 87, 181–186 (1994).
pubmed: 8208906
Recht, M., Liel, M. S., Turner, R. T., Klein, R. F. & Taylor, J. A. The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption. Haemophilia. 19, 908–912. https://doi.org/10.1111/hae.12195 (2013).
doi: 10.1111/hae.12195
pubmed: 23731369
Lu, D. et al. LRP1 suppresses bone resorption in mice by inhibiting the RANKL-Stimulated NF-kappaB and p38 pathways during osteoclastogenesis. J. Bone Min. Res. 33, 1773–1784. https://doi.org/10.1002/jbmr.3469 (2018).
doi: 10.1002/jbmr.3469
Gebetsberger, J., Schirmer, M., Wurzer, W. J. & Streif, W. Low bone Mineral Density in Hemophiliacs. Front. Med. (Lausanne). 9, 794456. https://doi.org/10.3389/fmed.2022.794456 (2022).
doi: 10.3389/fmed.2022.794456
pubmed: 35186990
Lin, X. et al. Pathogenesis and treatment of osteoporosis in patients with hemophilia. Arch. Osteoporos. 18, 17. https://doi.org/10.1007/s11657-022-01203-9 (2023).
doi: 10.1007/s11657-022-01203-9
pubmed: 36598583
pmcid: 9813251
Strauss, A. C. et al. Osteoporosis remains constant in patients with hemophilia-long-term course in consideration of comorbidities. Hamostaseologie. 43, 208–214. https://doi.org/10.1055/a-1972-8983 (2023).
doi: 10.1055/a-1972-8983
pubmed: 36863396
Wu, D. & Shen, S. Osteoporosis and associated risk factors in patients with severe hemophilia A: a case-control study from China. BMC Musculoskelet. Disord. 24, 657. https://doi.org/10.1186/s12891-023-06795-y (2023).
doi: 10.1186/s12891-023-06795-y
pubmed: 37592270
pmcid: 10433558
Wells, A. J. et al. A case-control study assessing bone mineral density in severe haemophilia A in the UK. Haemophilia 21, 109–115. https://doi.org/10.1111/hae.12565 (2015).
Alioglu, B. et al. Evaluation of bone mineral density in Turkish children with severe haemophilia A: Ankara hospital experience. Haemophilia. 18, 69–74. https://doi.org/10.1111/j.1365-2516.2011.02587.x (2012).
doi: 10.1111/j.1365-2516.2011.02587.x
pubmed: 21651678
Baud’huin, M. et al. Factor VIII-von willebrand factor Complex inhibits Osteoclastogenesis and Controls Cell Survival. J. Biol. Chem. 284, https://doi.org/10.1074/jbc.M109.030312 (2009).
Pai, Y. Y. et al. Risk of fractures, repeated fractures and osteoporotic fractures among patients with Hemophilia in Taiwan: a 14-Year Population-based Cohort Study. Int. J. Environ. Res. Public. Health. 20. https://doi.org/10.3390/ijerph20010525 (2022).
Klintman, J., Akesson, K. E., Holme, P. A. & Fischer, K. Bone mineral density in haemophilia - a multicentre study evaluating the impact of different replacement regimens. Haemophilia. 28, 239–246. https://doi.org/10.1111/hae.14487 (2022).
doi: 10.1111/hae.14487
pubmed: 34994489
Rodriguez-Merchan, E. C. Osteoporosis in hemophilia: what is its importance in clinical practice? Expert Rev. Hematol. 15, 697–710. https://doi.org/10.1080/17474086.2022.2108783 (2022).
doi: 10.1080/17474086.2022.2108783
pubmed: 35912904
Katsarou, O. et al. Increased bone resorption is implicated in the pathogenesis of bone loss in hemophiliacs: correlations with hemophilic arthropathy and HIV infection. Ann. Hematol. 89, 67–74. https://doi.org/10.1007/s00277-009-0759-x (2010).
doi: 10.1007/s00277-009-0759-x
pubmed: 19488753
Albayrak, C. & Albayrak, D. Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency. Blood Coagul Fibrinolysis. 26, 285–289. https://doi.org/10.1097/MBC.0000000000000237 (2015).
doi: 10.1097/MBC.0000000000000237
pubmed: 25485786
Linari, S. et al. Hypovitaminosis D and osteopenia/osteoporosis in a haemophilia population: a study in HCV/HIV or HCV infected patients. Haemophilia. 19, 126–133. https://doi.org/10.1111/j.1365-2516.2012.02899.x (2013).
doi: 10.1111/j.1365-2516.2012.02899.x
pubmed: 22776099
Dagli, M. et al. Evaluation of bone mineral density (BMD) and indicators of bone turnover in patients with hemophilia. Bosn J. Basic. Med. Sci. 18, 206–210. https://doi.org/10.17305/bjbms.2018.2335 (2018).
doi: 10.17305/bjbms.2018.2335
pubmed: 29236646
pmcid: 5988541
Goldscheitter, G., Recht, M., Sochacki, P., Manco-Johnson, M. & Taylor, J. A. Biomarkers of bone disease in persons with haemophilia. Haemophilia. 27, 149–155. https://doi.org/10.1111/hae.13986 (2021).
doi: 10.1111/hae.13986
pubmed: 32856388
Melchiorre, D. et al. RANK-RANKL-OPG in hemophilic arthropathy: from clinical and imaging diagnosis to histopathology. J. Rheumatol. 39, 1678–1686. https://doi.org/10.3899/jrheum.120370 (2012).
doi: 10.3899/jrheum.120370
pubmed: 22753650
Ivanova, H. A., Grudeva-Popova, Z., Deneva, T., Tsvetkova, S. & Mateva, N. A single-center study of bone mineral density in adult patients with severe hemophilia A in correlation with markers of bone metabolism. Folia Med. (Plovdiv). 65, 87–92. https://doi.org/10.3897/folmed.65.e75414 (2023).
doi: 10.3897/folmed.65.e75414
pubmed: 36855979
Alito, A. et al. Haemophilia and Fragility fractures: from pathogenesis to Multidisciplinary Approach. Int. J. Mol. Sci. 24. https://doi.org/10.3390/ijms24119395 (2023).
Sivagurunathan, S. et al. Thrombin inhibits osteoclast differentiation through a non-proteolytic mechanism. J. Mol. Endocrinol. 50, 347–359. https://doi.org/10.1530/JME-12-0177 (2013).
doi: 10.1530/JME-12-0177
pubmed: 23419317
Lari, R., Kitchener, P. D. & Hamilton, J. A. The proliferative human monocyte subpopulation contains osteoclast precursors. Arthritis Res. Ther. 11, R23. https://doi.org/10.1186/ar2616 (2009).
doi: 10.1186/ar2616
pubmed: 19222861
pmcid: 2688256
Li, J. et al. Inhibition of Osteoclastogenesis and Bone Resorption in vitro and in vivo by a prenylflavonoid xanthohumol from hops. Sci. Rep. 5, 17605. https://doi.org/10.1038/srep17605 (2015).
doi: 10.1038/srep17605
pubmed: 26620037
pmcid: 4664947
Lenting, P. J., Denis, C. V. & Christophe, O. D. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood. 130, 2463–2468. https://doi.org/10.1182/blood-2017-08-801662 (2017).
doi: 10.1182/blood-2017-08-801662
pubmed: 29042366
Komano, Y., Nanki, T., Hayashida, K., Taniguchi, K. & Miyasaka, N. Identification of a human peripheral blood monocyte subset that differentiates into osteoclasts. Arthritis Res. Ther. 8, R152. https://doi.org/10.1186/ar2046 (2006).
doi: 10.1186/ar2046
pubmed: 16987426
pmcid: 1779441
Puchner, A. et al. Non-classical monocytes as mediators of tissue destruction in arthritis. Ann. Rheum. Dis. 77, 1490–1497. https://doi.org/10.1136/annrheumdis-2018-213250 (2018).
doi: 10.1136/annrheumdis-2018-213250
pubmed: 29959183
Taves, S. et al. Hemophilia A and B mice, but not VWF(-/-)mice, display bone defects in congenital development and remodeling after injury. Sci. Rep. 9, 14428. https://doi.org/10.1038/s41598-019-50787-9 (2019).
doi: 10.1038/s41598-019-50787-9
pubmed: 31594977
pmcid: 6783554
De Benedetti, F. et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 54, 3551–3563. https://doi.org/10.1002/art.22175 (2006).
doi: 10.1002/art.22175
pubmed: 17075861
Citla-Sridhar, D., Sidonio, R. F., Ahuja, S. P. & Jr. & Bone health in haemophilia carriers and persons with Von Willebrand disease: a large database analysis. Haemophilia. 28, 671–678. https://doi.org/10.1111/hae.14565 (2022).
doi: 10.1111/hae.14565
pubmed: 35416396
Pepe, J. et al. Characterization of Extracellular vesicles in osteoporotic patients compared to osteopenic and healthy controls. J. Bone Min. Res. 37, 2186–2200. https://doi.org/10.1002/jbmr.4688 (2022).
doi: 10.1002/jbmr.4688
Hodge, J. M., Kirkland, M. A. & Nicholson, G. C. Multiple roles of M-CSF in human osteoclastogenesis. J. Cell. Biochem. 102, 759–768. https://doi.org/10.1002/jcb.21331 (2007).
doi: 10.1002/jcb.21331
pubmed: 17516513
Sprangers, S., Schoenmaker, T., Cao, Y., Everts, V. & de Vries, T. J. Different blood-borne human osteoclast precursors respond in distinct ways to IL-17A. J. Cell. Physiol. 231, 1249–1260. https://doi.org/10.1002/jcp.25220 (2016).
doi: 10.1002/jcp.25220
pubmed: 26491867
Xue, J. et al. CD14(+)CD16(-) monocytes are the main precursors of osteoclasts in rheumatoid arthritis via expressing Tyro3TK. Arthritis Res. Ther. 22, 221. https://doi.org/10.1186/s13075-020-02308-7 (2020).
doi: 10.1186/s13075-020-02308-7
pubmed: 32958023
pmcid: 7507256
Blair, H. A. & Emicizumab A review in Haemophilia A. Drugs. 79, 1697–1707. https://doi.org/10.1007/s40265-019-01200-2 (2019).
doi: 10.1007/s40265-019-01200-2
pubmed: 31542880
Mansouritorghabeh, H. et al. Reduced bone density in individuals with severe hemophilia B. Int. J. Rheum. Dis. 12, 125–129. https://doi.org/10.1111/j.1756-185X.2009.01394.x (2009).
doi: 10.1111/j.1756-185X.2009.01394.x
pubmed: 20374329
Anagnostis, P. et al. The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B. Haemophilia. 20, 268–275. https://doi.org/10.1111/hae.12271 (2014).
doi: 10.1111/hae.12271
pubmed: 24118364
Weitzmann, M. N. et al. Reduced bone formation in males and increased bone resorption in females drive bone loss in hemophilia A mice. Blood Adv. 3, 288–300. https://doi.org/10.1182/bloodadvances.2018027557 (2019).
doi: 10.1182/bloodadvances.2018027557
pubmed: 30700417
pmcid: 6373738
Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl. J. Med. 361, 756–765. https://doi.org/10.1056/NEJMoa0809493 (2009).
doi: 10.1056/NEJMoa0809493
pubmed: 19671655
Pagel, C. N. et al. Inhibition of osteoblast apoptosis by thrombin. Bone. 33, 733–743. https://doi.org/10.1016/s8756-3282(03)00209-6 (2003).
doi: 10.1016/s8756-3282(03)00209-6
pubmed: 14555279
Tatakis, D. N., Dolce, C. & Dziak, R. Thrombin’s effects on osteoblastic cells. I. Cytosolic calcium and phosphoinositides. Biochem. Biophys. Res. Commun. 164, 119–127. https://doi.org/10.1016/0006-291x(89)91691-4 (1989).
doi: 10.1016/0006-291x(89)91691-4
pubmed: 2553011
Mackie, E. J. et al. Protease-activated receptors in the musculoskeletal system. Int. J. Biochem. Cell. Biol. 40, 1169–1184. https://doi.org/10.1016/j.biocel.2007.12.003 (2008).
doi: 10.1016/j.biocel.2007.12.003
pubmed: 18243039
Smith, R. et al. Activation of protease-activated receptor-2 leads to inhibition of osteoclast differentiation. J. Bone Min. Res. 19, 507–516. https://doi.org/10.1359/JBMR.0301248 (2004).
doi: 10.1359/JBMR.0301248
Kowal, R. C., Herz, J., Goldstein, J. L., Esser, V. & Brown, M. S. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc. Natl. Acad. Sci. U S A. 86, 5810–5814. https://doi.org/10.1073/pnas.86.15.5810 (1989).
doi: 10.1073/pnas.86.15.5810
pubmed: 2762297
pmcid: 297720
Lillis, A. P., Van Duyn, L. B., Murphy-Ullrich, J. E. & Strickland, D. K. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 88, 887–918. https://doi.org/10.1152/physrev.00033.2007 (2008).
doi: 10.1152/physrev.00033.2007
pubmed: 18626063
Sacco, M. et al. The p.P1127S pathogenic variant lowers Von Willebrand factor levels through higher affinity for the macrophagic scavenger receptor LRP1: clinical phenotype and pathogenic mechanisms. J. Thromb. Haemost. 20, 1818–1829. https://doi.org/10.1111/jth.15765 (2022).
doi: 10.1111/jth.15765
pubmed: 35596664
pmcid: 9545986
Rastegarlari, G. et al. Macrophage LRP1 contributes to the clearance of Von Willebrand factor. Blood. 119, 2126–2134. https://doi.org/10.1182/blood-2011-08-373605 (2012).
doi: 10.1182/blood-2011-08-373605
pubmed: 22234691
Kohara, Y., Haraguchi, R., Kitazawa, R. & Kitazawa, S. Knockdown of Lrp1 in RAW264 cells inhibits osteoclast differentiation and osteoclast-osteoblast interactions in vitro. Biochem. Biophys. Res. Commun. 523, 961–965. https://doi.org/10.1016/j.bbrc.2020.01.065 (2020).
doi: 10.1016/j.bbrc.2020.01.065
pubmed: 31964526
Jesty, J. Analysis of the generation and inhibition of activated coagulation factor X in pure systems and in human plasma. J. Biol. Chem. 261, 8695–8702 (1986).
doi: 10.1016/S0021-9258(19)84436-8
pubmed: 3722168
Tarandovskiy, I. D. et al. Investigation of thrombin concentration at the time of clot formation in simultaneous thrombin and fibrin generation assays. Sci. Rep. 14, 9225. https://doi.org/10.1038/s41598-023-47694-5 (2024).
doi: 10.1038/s41598-023-47694-5
pubmed: 38649717
pmcid: 11035586
van Schooten, C. J. et al. Macrophages contribute to the cellular uptake of Von Willebrand factor and factor VIII in vivo. Blood. 112, 1704–1712. https://doi.org/10.1182/blood-2008-01-133181 (2008).
doi: 10.1182/blood-2008-01-133181
pubmed: 18559674
Drakeford, C. et al. Von Willebrand factor links primary hemostasis to innate immunity. Nat. Commun. 13, 6320. https://doi.org/10.1038/s41467-022-33796-7 (2022).
doi: 10.1038/s41467-022-33796-7
pubmed: 36329021
pmcid: 9633696
Repesse, Y. et al. Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. J. Thromb. Haemost. 5, 1469–1476. https://doi.org/10.1111/j.1538-7836.2007.02591.x (2007).
doi: 10.1111/j.1538-7836.2007.02591.x
pubmed: 17445092