Hyperthyroidism-driven bone loss depends on BMP receptor Bmpr1a expression in osteoblasts.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
08 May 2024
08 May 2024
Historique:
received:
25
04
2023
accepted:
22
04
2024
medline:
9
5
2024
pubmed:
9
5
2024
entrez:
8
5
2024
Statut:
epublish
Résumé
Hyperthyroidism is a well-known trigger of high bone turnover that can lead to the development of secondary osteoporosis. Previously, we have shown that blocking bone morphogenetic protein (BMP) signaling systemically with BMPR1A-Fc can prevent bone loss in hyperthyroid mice. To distinguish between bone cell type-specific effects, conditional knockout mice lacking Bmpr1a in either osteoclast precursors (LysM-Cre) or osteoprogenitors (Osx-Cre) were rendered hyperthyroid and their bone microarchitecture, strength and turnover were analyzed. While hyperthyroidism in osteoclast precursor-specific Bmpr1a knockout mice accelerated bone resorption leading to bone loss just as in wildtype mice, osteoprogenitor-specific Bmpr1a deletion prevented an increase of bone resorption and thus osteoporosis with hyperthyroidism. In vitro, wildtype but not Bmpr1a-deficient osteoblasts responded to thyroid hormone (TH) treatment with increased differentiation and activity. Furthermore, we found an elevated Rankl/Opg ratio with TH excess in osteoblasts and bone tissue from wildtype mice, but not in Bmpr1a knockouts. In line, expression of osteoclast marker genes increased when osteoclasts were treated with supernatants from TH-stimulated wildtype osteoblasts, in contrast to Bmpr1a-deficient cells. In conclusion, we identified the osteoblastic BMP receptor BMPR1A as a main driver of osteoporosis in hyperthyroid mice promoting TH-induced osteoblast activity and potentially its coupling to high osteoclastic resorption.
Identifiants
pubmed: 38719881
doi: 10.1038/s42003-024-06227-0
pii: 10.1038/s42003-024-06227-0
doi:
Substances chimiques
Bone Morphogenetic Protein Receptors, Type I
EC 2.7.11.30
Bmpr1a protein, mouse
EC 2.7.11.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
548Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : LA 4945/1-1
Informations de copyright
© 2024. The Author(s).
Références
Taylor, P. N. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 14, 301–316 (2018).
pubmed: 29569622
doi: 10.1038/nrendo.2018.18
Bassett, J. H. D. & Williams, G. R. Role of thyroid hormones in skeletal development and bone maintenance. Endocr. Rev. 37, 135–187 (2016).
pubmed: 26862888
pmcid: 4823381
doi: 10.1210/er.2015-1106
Tsourdi, E., Rijntjes, E., Köhrle, J., Hofbauer, L. C. & Rauner, M. Hyperthyroidism and hypothyroidism in male mice and their effects on bone mass, bone turnover, and the wnt inhibitors sclerostin and Dickkopf-1. Endocrinology 156, 3517–3527 (2015).
pubmed: 26218891
doi: 10.1210/en.2015-1073
Blum, M. R. et al. Subclinical thyroid dysfunction and fracture risk a meta-analysis. JAMA 313, 2055–2065 (2015).
pubmed: 26010634
pmcid: 4729304
doi: 10.1001/jama.2015.5161
Abrahamsen, B. et al. Low serum thyrotropin level and duration of suppression as a predictor of major osteoporotic fractures-The OPENTHYRO Register Cohort. https://doi.org/10.1002/jbmr.2244 (2014).
Vestergaard, P. & Mosekilde, L. Hyperthyroidism, bone mineral, and fracture risk—a meta-analysis. Thyroid 13, 585–593 (2003).
pubmed: 12930603
doi: 10.1089/105072503322238854
Vestergaard, P. & Mosekilde, L. Fractures in patients with hyperthyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients. 12, 411–419. https://home.liebertpub.com/thy (2004).
Vestergaard, P., Rejnmark, L. & Mosekilde, L. Influence of hyper- and hypothyroidism, and the effects of treatment with antithyroid drugs and levothyroxine on fracture risk. Calcif. Tissue Int. 77, 139–144 (2005).
pubmed: 16151671
doi: 10.1007/s00223-005-0068-x
Fratzl-Zelman, N. et al. Effects of triiodothyronine on the morphology of cells and matrix, the localization of alkaline phosphatase, and the frequency of apoptosis in long-term cultures of MC3T3-E1 cells. Bone 20, 225–236 (1997).
pubmed: 9071473
doi: 10.1016/S8756-3282(96)00367-5
Klaushofer, K. et al. The regulatory role of thyroid hormones in bone cell growth and differentiation. J. Nutr. 125, 1996S–2003S (2018).
doi: 10.1093/jn/125.suppl_7.1996S
Varga, F. et al. T3 affects expression of collagen I and collagen cross-linking in bone cell cultures. Biochem. Biophys. Res. Commun. 402, 180–185 (2010).
pubmed: 20707983
pmcid: 3025330
doi: 10.1016/j.bbrc.2010.08.022
Banovac, K. & Koren, E. Triiodothyronine stimulates the release of membrane-bound alkaline phosphatase in osteoblastic cells. Calcif. Tissue Int. 67, 460–465 (2000).
pubmed: 11289695
doi: 10.1007/s002230001171
Tokuda, K. et al. (-)-Epigallocatechin gallate inhibits thyroid hormone-stimulated osteocalcin synthesis in osteoblasts. Mol. Med. Rep. 4, 297–300 (2011).
pubmed: 21468567
doi: 10.3892/mmr.2011.421
Cray, J. J., Khaksarfard, K., Weinberg, S. M., Elsalanty, M. & Yu, J. C. Effects of thyroxine exposure on osteogenesis in mouse calvarial pre-osteoblasts. PLoS One 8, e69067 (2013).
pubmed: 23935926
pmcid: 3720861
doi: 10.1371/journal.pone.0069067
Huang, B. K., Golden, L. A., Tarjan, G., Madison, L. D. & Stern, P. H. Insulin-like growth factor I Production Is essential for anabolic effects of thyroid hormone in osteoblasts. J. Bone Mineral Res. 15, 188–197 (2010).
doi: 10.1359/jbmr.2000.15.2.188
Lademann, F. et al. Lack of the thyroid hormone transporter Mct8 in osteoblast and osteoclast progenitors increases trabecular bone in male mice. Thyroid 30, 329–342 (2020).
pubmed: 31910109
doi: 10.1089/thy.2019.0271
Lademann, F. et al. The thyroid hormone transporter MCT10 is a novel regulator of trabecular bone mass and bone turnover in male mice. Endocrinology https://doi.org/10.1210/ENDOCR/BQAB218 (2021).
Allain, T. J., Yen, P. M., Flanagan, A. M. & McGregor, A. M. The isoform-specific expression of the tri-iodothyronine receptor in osteoblasts and osteoclasts. Eur. J. Clin. Investig. 26, 418–425 (1996).
doi: 10.1046/j.1365-2362.1996.160289.x
Krieger, N. S., Stappenbeck, T. S. & Stern, P. H. Characterization of specific thyroid hormone receptors in bone. J Bone Miner. Res. 3, 473–478 (1988).
pubmed: 3223358
doi: 10.1002/jbmr.5650030415
Williams, A. J. et al. Iodothyronine deiodinase enzyme activities in bone. Bone 43, 126–134 (2008).
pubmed: 18468505
pmcid: 2681075
doi: 10.1016/j.bone.2008.03.019
Klaushofer, K. et al. Bone-resorbing activity of thyroid hormones is related to prostaglandin production in cultured neonatal mouse calvaria. J. Bone Miner. Res. 4, 305–312 (2009).
doi: 10.1002/jbmr.5650040304
Mundy, G. R., Shapiro, J. L., Bandelin, J. G., Canalis, E. M. & Raisz, L. G. Direct stimulation of bone resorption by thyroid hormones. J. Clin. Investig. 58, 529–534 (1976).
pubmed: 182721
pmcid: 333209
doi: 10.1172/JCI108497
Allain, T. J., Chambers, T. J., Flanagan, A. M. & McGregor, A. M. Tri-iodothyronine stimulates rat osteoclastic bone resorption by an indirect effect. J. Endocrinol. 133, 327–331 (1992).
pubmed: 1613434
doi: 10.1677/joe.0.1330327
Siddiqi, A., Burrin, J. M., Wood, D. F. & Monson, J. P. Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and osteoblast-like cells. J. Endocrinol. 157, 453–461 (1998).
pubmed: 9691978
doi: 10.1677/joe.0.1570453
Miura, M. et al. A Novel Interaction between Thyroid Hormones and 1,25(OH)2D3 in Osteoclast Formation. Biochem. Biophys. Res. Commun. 291, 987–994 (2002).
pubmed: 11866463
doi: 10.1006/bbrc.2002.6561
Lademann, F. et al. Disruption of BMP signaling prevents hyperthyroidism-induced bone loss in male mice. J. Bone Miner. Res. https://doi.org/10.1002/jbmr.4092 (2020).
Beederman, M. et al. BMP signaling in mesenchymal stem cell differentiation and bone formation. J. Biomed. Sci. Eng. 6, 32–52 (2013).
pubmed: 26819651
pmcid: 4725591
doi: 10.4236/jbise.2013.68A1004
Wu, M., Chen, G. & Li, Y. P. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 4, 16009 (2016).
pubmed: 27563484
pmcid: 4985055
doi: 10.1038/boneres.2016.9
Kamiya, N. et al. Disruption of BMP signaling in osteoblasts through Type IA Receptor (BMPRIA) increases bone mass*. J. Bone Miner. Res. 23, 2007–2017 (2008).
pubmed: 18684091
pmcid: 2686924
doi: 10.1359/jbmr.080809
Kamiya, N. et al. Targeted disruption of BMP signaling through type IA receptor (BMPR1A) in osteocyte suppresses SOST and RANKL, leading to dramatic increase in bone mass, bone mineral density and mechanical strength. Bone 91, 53–63 (2016).
pubmed: 27402532
doi: 10.1016/j.bone.2016.07.002
Zhang, Y. et al. Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments. Bone 88, 74–84 (2016).
pubmed: 27113526
pmcid: 4899267
doi: 10.1016/j.bone.2016.04.022
Shi, C. et al. Bone morphogenetic protein signaling through ACVR1 and BMPR1A negatively regulates bone mass along with alterations in bone composition. J. Struct. Biol. 201, 237–246 (2018).
pubmed: 29175363
doi: 10.1016/j.jsb.2017.11.010
Lademann, F., Hofbauer, L. C. & Rauner, M. The bone morphogenetic protein pathway: the osteoclastic perspective. Front. Cell Dev. Biol. 8, 586031 (2020).
pubmed: 33178699
pmcid: 7597383
doi: 10.3389/fcell.2020.586031
Bordukalo-Nikšić, T., Kufner, V. & Vukičević, S. The role Of BMPs in the regulation of osteoclasts resorption and bone remodeling: from experimental models to clinical applications. Front. Immunol. 13, 1–16 (2022).
doi: 10.3389/fimmu.2022.869422
Boergermann, J. H., Kopf, J., Yu, P. B. & Knaus, P. Dorsomorphin and LDN-193189 inhibit BMP-mediated Smad, p38 and Akt signalling in C2C12 cells. Int. J. Biochem. Cell Biol. 42, 1802–1807 (2010).
pubmed: 20691279
pmcid: 6164168
doi: 10.1016/j.biocel.2010.07.018
Okamoto, M. et al. Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. J. Bone Miner. Res. 26, 2511–2522 (2011).
pubmed: 21786321
doi: 10.1002/jbmr.477
Tasca, A. et al. Smad1/5 and Smad4 expression are important for osteoclast differentiation. J. Cell Biochem. 116, 1350–1360 (2015).
pubmed: 25711193
pmcid: 4431909
doi: 10.1002/jcb.25092
Kim, J. M., Lin, C., Stavre, Z., Greenblatt, M. B. & Shim, J. H. Osteoblast-Osteoclast Communication and Bone Homeostasis. Cells 9, 2073 (2020).
Kamiya, N. et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development 135, 3801–3811 (2008).
pubmed: 18927151
doi: 10.1242/dev.025825
Iura, A. et al. Mechanical loading synergistically increases trabecular bone volume and improves mechanical properties in the mouse when BMP signaling is specifically ablated in osteoblasts. PLoS One 10, e0141345 (2015).
pubmed: 26489086
pmcid: 4619208
doi: 10.1371/journal.pone.0141345
Arponen, M., Jalava, N., Widjaja, N. & Ivaska, K. K. Glucose transporters GLUT1, GLUT3, and GLUT4 have different effects on osteoblast proliferation and metabolism. Front. Physiol. 13, 1035516 (2022).
Li, A. et al. Pharmacologic calcitriol inhibits osteoclast lineage commitment via the BMP-Smad1 and IκB-NF-κB pathways. J. Bone Miner. Res. 32, 1406–1420 (2017).
pubmed: 28370465
doi: 10.1002/jbmr.3146
Tsourdi, E. et al. The role of Dickkopf-1 in thyroid hormone-induced changes of bone remodeling in male mice. Endocrinology 160, 664–674 (2019).
pubmed: 30689850
doi: 10.1210/en.2018-00998
Tsourdi, E. et al. Sclerostin blockade and zoledronic acid improve bone mass and strength in male mice with exogenous hyperthyroidism. Endocrinology 158, 3765–3777 (2017).
pubmed: 28973221
doi: 10.1210/en.2017-00247
Mishina, Y. et al. Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J. Biol. Chem. 279, 27560–27566 (2004).
pubmed: 15090551
doi: 10.1074/jbc.M404222200
Biswas, S. et al. BMPRIA is required for osteogenic differentiation and RANKL expression in adult bone marrow mesenchymal stromal cells OPEN. Sci. Rep. 8, 8475 (2018).
pubmed: 29855498
pmcid: 5981611
doi: 10.1038/s41598-018-26820-8
Bao, Q. et al. Disruption of bone morphogenetic protein type IA receptor in osteoblasts impairs bone quality and bone strength in mice. Cell Tissue Res. 374, 263–273 (2018).
pubmed: 29987355
doi: 10.1007/s00441-018-2873-3
Lindsey, R. C. & Mohan, S. Thyroid hormone acting via TRβ induces expression of browning genes in mouse bone marrow adipose tissue. Endocrine 56, 109–120 (2017).
pubmed: 28229360
pmcid: 8745377
doi: 10.1007/s12020-017-1265-x
Foster, M. P., Montecino-Rodriguez, E. & Dorshkind, K. Proliferation of bone marrow Pro-B cells is dependent on stimulation by the pituitary/thyroid axis. J. Immunol. 163, 5883–5890 (1999).
pubmed: 10570273
doi: 10.4049/jimmunol.163.11.5883
Park, S. et al. Defective erythropoiesis caused by mutations of the thyroid hormone receptor α gene. PLoS Genet. 13, e1006991 (2017).
pubmed: 28910278
pmcid: 5621702
doi: 10.1371/journal.pgen.1006991
Malgor, L. et al. Direct effects of thyroid hormones on bone marrow erythroid cells of rats. Blood 45, 671–679 (1975).
pubmed: 1120189
doi: 10.1182/blood.V45.5.671.671
Volke, L. & Krause, K. Effect of thyroid hormones on adipose tissue flexibility. Eur. Thyroid. J. 10, 1–9 (2021).
pubmed: 33777816
Cipriani, C. et al. The interplay between bone and glucose metabolism. Front. Endocrinol. (Lausanne) 11, 122 (2020).
Donat, A. et al. Glucose metabolism in osteoblasts in healthy and pathophysiological conditions. Int. J. Mol. Sci. 22, 4120 (2021).
pubmed: 33923498
pmcid: 8073638
doi: 10.3390/ijms22084120
Zoidis, E., Ghirlanda-Keller, C. & Schmid, C. Triiodothyronine stimulates glucose transport in bone cells. Endocrine 41, 501–511 (2012).
pubmed: 22258767
doi: 10.1007/s12020-012-9594-2
Lademann, F., Rauner, M., Bonnet, N., Hofbauer, L. C. & Tsourdi, E. Low Bone Turnover Due to Hypothyroidism or Anti-Resorptive Treatment Does Not Affect Whole-Body Glucose Homeostasis in Male Mice. J. Pers. Med. 12, 1462 (2022).
Lee, S. Y., Abel, E. D. & Long, F. Glucose metabolism induced by Bmp signaling is essential for murine skeletal development. Nat. Commun. 9, 1–11 (2018).
doi: 10.1038/s41467-018-07316-5
Schreiber, I. et al. BMPs as new insulin sensitizers: enhanced glucose uptake in mature 3T3-L1 adipocytes via PPARγ and GLUT4 upregulation. Sci. Rep. 7, 1–13 (2017).
doi: 10.1038/s41598-017-17595-5
Kamiya, N. et al. Controversy of physiological vs. pharmacological effects of BMP signaling: constitutive activation of BMP type IA receptor-dependent signaling in osteoblast lineage enhances bone formation and resorption, not affecting net bone mass. Bone 138, 115513 (2020).
pubmed: 32603910
pmcid: 7423725
doi: 10.1016/j.bone.2020.115513
Ikebuchi, Y. et al. Coupling of bone resorption and formation by RANKL reverse signalling. Nature 561, 195–200 (2018).
pubmed: 30185903
doi: 10.1038/s41586-018-0482-7
Ma, Q. et al. Mature osteoclast-derived apoptotic bodies promote osteogenic differentiation via RANKL-mediated reverse signaling. J. Biol. Chem. 294, 11240–11247 (2019).
pubmed: 31167789
pmcid: 6643026
doi: 10.1074/jbc.RA119.007625
Abram, C. L., Roberge, G. L., Hu, Y. & Lowell, C. A. Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice. J. Immunol. Methods 408, 89–100 (2014).
pubmed: 24857755
pmcid: 4105345
doi: 10.1016/j.jim.2014.05.009
Chen, J. et al. Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice. PLoS One 9, e85161 (2014).
pubmed: 24454809
pmcid: 3893188
doi: 10.1371/journal.pone.0085161
Kitaura, H. et al. Molecular sciences osteocyte-related cytokines regulate osteoclast formation and bone resorption. https://doi.org/10.3390/ijms21145169 .
Wölfel, E. M. et al. Reduced bone mass and increased osteocyte TRAP activity, but not low mineralized matrix around osteocyte lacunae, are restored after recovery from exogenous hyperthyroidism in male mice. J. Bone Miner. Res. https://doi.org/10.1002/JBMR.4736 (2022).
Couasnay, G., Madel, M. B., Lim, J., Lee, B. & Elefteriou, F. Sites of Cre-recombinase activity in mouse lines targeting skeletal cells. J. Bone Miner. Res. 36, 1661–1679 (2021).
pubmed: 34278610
doi: 10.1002/jbmr.4415
Bonewald, L. F. The amazing osteocyte. J. Bone Miner. Res. 26, 229–238 (2011).
pubmed: 21254230
doi: 10.1002/jbmr.320
Mishina, Y., Hanks, M. C., Miura, S., Tallquist, M. D. & Behringer, R. R. Generation of Bmpr/Alk3 conditional knockout mice. Genesis 32, 69–72 (2002).
pubmed: 11857780
doi: 10.1002/gene.10038
Rodda, S. J. & McMahon, A. P. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development 133, 3231–3244 (2006).
pubmed: 16854976
doi: 10.1242/dev.02480
Wang, L., Mishina, Y. & Liu, F. Osterix-Cre transgene causes craniofacial bone development defect. Calcif. Tissue Int. 96, 129 (2015).
pubmed: 25550101
doi: 10.1007/s00223-014-9945-5
Colditz, J. et al. Postnatal skeletal deletion of Dickkopf-1 Increases bone formation and bone volume in male and female mice, despite increased sclerostin expression. J Bone Miner Res 33, 1698–1707 (2018).
pubmed: 29734465
doi: 10.1002/jbmr.3463
Rauner, M. et al. Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling. Nat. Metab. 1, 111–124 (2019).
pubmed: 30886999
pmcid: 6420074
doi: 10.1038/s42255-018-0005-8
Clausen, B. E. et al. Conditional gene targeting in macrophage and granulocytes using LysMcre mice. Transgenic Res. 96, 317–330 (2001).
Lademann, F., Tsourdi, E., Hofbauer, L. C. & Rauner, M. Bone cell-specific deletion of thyroid hormone transporter Mct8 distinctly regulates bone volume in young versus adult male mice. Bone 159, 116375 (2022).
pubmed: 35240348
doi: 10.1016/j.bone.2022.116375
Dempster, D. W. et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 28, 2–17 (2013).
pubmed: 23197339
doi: 10.1002/jbmr.1805
Lademann, F., Tsourdi, E., Hofbauer, L. C. & Rauner, M. Thyroid hormone receptor Thra and Thrb knockout differentially affects osteoblast biology and thyroid hormone responsiveness in vitro. J. Cell Biochem. https://doi.org/10.1002/jcb.30500 (2023).