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Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis

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Abstract

Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor β1 (TGF-β1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF-β1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-β1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-β1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-β activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-β type II receptor (TβRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-β1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease.

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Figure 1: Upregulated TGF-β signaling in the subchondral bone is associated with changes of subchondral bone architecture in ACLT mice.
Figure 2: CED mice with transgenic activating mutation of TGF-β1 show a knee osteoarthritis phenotype.
Figure 3: TβRI inhibitor stabilizes the subchondral bone microarchitecture and attenuates articular cartilage degeneration in ACLT mice.
Figure 4: TβRI inhibitor reduces uncoupled bone formation and angiogenesis in ACLT mice.
Figure 5: Local subchondral administration of antibody to TGF-β reduces aberrant subchondral bone formation and articular cartilage degeneration in ACLT rats.
Figure 6: Inducible knockout of Tgfbr2 in nestin-positive cells results in less change in subchondral bone and articular cartilage relative to WT mice after ACLT.

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References

  1. Hootman, J.M. & Helmick, C.G. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum. 54, 226–229 (2006).

    Article  PubMed  Google Scholar 

  2. van den Berg, W.B. Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthritis Cartilage 19, 338–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Berenbaum, F. Osteoarthritis year 2010 in review: pharmacological therapies. Osteoarthritis Cartilage 19, 361–365 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Hawker, G.A., Mian, S., Bednis, K. & Stanaitis, I. Osteoarthritis year 2010 in review: non-pharmacologic therapy. Osteoarthritis Cartilage 19, 366–374 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Saito, T. et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med. 16, 678–686 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Yang, S. et al. Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction. Nat. Med. 16, 687–693 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674–1679 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Glasson, S.S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Neuhold, L.A. et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J. Clin. Invest. 107, 35–44 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lories, R.J. & Luyten, F.P. The bone-cartilage unit in osteoarthritis. Nat. Rev. Rheumatol. 7, 43–49 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Madry, H., van Dijk, C.N. & Mueller-Gerbl, M. The basic science of the subchondral bone. Knee Surg. Sports Traumatol. Arthrosc. 18, 419–433 (2010).

    Article  PubMed  Google Scholar 

  12. Burr, D.B. & Radin, E.L. Microfractures and microcracks in subchondral bone: are they relevant to osteoarthrosis? Rheum. Dis. Clin. North Am. 29, 675–685 (2003).

    Article  PubMed  Google Scholar 

  13. Stein, V. et al. Pattern of joint damage in persons with knee osteoarthritis and concomitant ACL tears. Rheumatol. Int. 32, 1197–1208 (2012).

    Article  PubMed  Google Scholar 

  14. Amin, S. et al. Complete anterior cruciate ligament tear and the risk for cartilage loss and progression of symptoms in men and women with knee osteoarthritis. Osteoarthritis Cartilage 16, 897–902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hill, C.L. et al. Cruciate ligament integrity in osteoarthritis of the knee. Arthritis Rheum. 52, 794–799 (2005).

    Article  PubMed  Google Scholar 

  16. Suri, S. & Walsh, D.A. Osteochondral alterations in osteoarthritis. Bone 51, 204–211 (2012).

    Article  PubMed  Google Scholar 

  17. Hunter, D.J. et al. Increase in bone marrow lesions associated with cartilage loss: a longitudinal magnetic resonance imaging study of knee osteoarthritis. Arthritis Rheum. 54, 1529–1535 (2006).

    Article  PubMed  Google Scholar 

  18. Dreier, R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res. Ther. 12, 216 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Tchetina, E.V. Developmental mechanisms in articular cartilage degradation in osteoarthritis. Arthritis 2011, 683970 (2011).

    Article  PubMed  Google Scholar 

  20. Blaney Davidson, E.N., van der Kraan, P.M. & van den Berg, W.B. TGF-β and osteoarthritis. Osteoarthritis Cartilage 15, 597–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Yang, X. et al. TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J. Cell Biol. 153, 35–46 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu, Q. et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum. 58, 3132–3144 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Blaney Davidson, E.N. et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J. Immunol. 182, 7937–7945 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. van der Kraan, P.M., Blaney Davidson, E.N., Blom, A. & van den Berg, W.B. TGF-β signaling in chondrocyte terminal differentiation and osteoarthritis: modulation and integration of signaling pathways through receptor-Smads. Osteoarthritis Cartilage 17, 1539–1545 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. van der Kraan, P.M., Blaney Davidson, E.N. & van den Berg, W.B. A role for age-related changes in TGFβ signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res. Ther. 12, 201 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Scharstuhl, A. et al. Inhibition of endogenous TGF-β during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J. Immunol. 169, 507–514 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Scharstuhl, A., Vitters, E.L., van der Kraan, P.M. & van den Berg, W.B. Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor β/bone morphogenetic protein inhibitors during experimental osteoarthritis. Arthritis Rheum. 48, 3442–3451 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Tang, Y. et al. TGF-β1–induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med. 15, 757–765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hahn, M., Vogel, M., Pompesius-Kempa, M. & Delling, G. Trabecular bone pattern factor—a new parameter for simple quantification of bone microarchitecture. Bone 13, 327–330 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Pritzker, K.P. et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage 14, 13–29 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Whyte, M.P. et al. Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFβ1 encoding transforming growth factor β 1 and a missense change in TNFSF11 encoding RANK ligand. J. Bone Miner. Res. 26, 920–933 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Lotz, M. Osteoarthritis year 2011 in review: biology. Osteoarthritis Cartilage 20, 192–196 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Wiese, C. et al. Nestin expression—a property of multi-lineage progenitor cells? Cell Mol. Life Sci. 61, 2510–2522 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Kamekura, S. et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13, 632–641 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Goumans, M.J. et al. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 21, 1743–1753 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lorts, A., Schwanekamp, J.A., Baudino, T.A., McNally, E.M. & Molkentin, J.D. Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-β pathway. Proc. Natl. Acad. Sci. USA 109, 10978–10983 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Edwards, J.R. et al. Inhibition of TGF-β signaling by 1D11 antibody treatment increases bone mass and quality in vivo. J. Bone Miner. Res. 25, 2419–2426 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Ma, Y., Li, W.Z., Guan, S.X., Lai, X.P. & Chen, D.W. Evaluation of tetrandrine sustained release calcium alginate gel beads in vitro and in vivo. Yakugaku Zasshi 129, 851–854 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Downs, E.C., Robertson, N.E., Riss, T.L. & Plunkett, M.L. Calcium alginate beads as a slow-release system for delivering angiogenic molecules in vivo and in vitro. J. Cell Physiol. 152, 422–429 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Zhang, M. et al. Smad3 prevents β-catenin degradation and facilitates β-catenin nuclear translocation in chondrocytes. J. Biol. Chem. 285, 8703–8710 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li, T.F. et al. Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J. Bone Miner. Res. 21, 4–16 (2006).

    Article  PubMed  CAS  Google Scholar 

  44. Sekiya, I. et al. Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis. J. Orthop. Res. 30, 943–949 (2012).

    Article  PubMed  Google Scholar 

  45. Koyama, N. et al. Pluripotency of mesenchymal cells derived from synovial fluid in patients with temporomandibular joint disorder. Life Sci. 89, 741–747 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Hunter, D.J. et al. Bone marrow lesions from osteoarthritis knees are characterized by sclerotic bone that is less well mineralized. Arthritis Res. Ther. 11, R11 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Cunha, S.I. & Pietras, K. ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood 117, 6999–7006 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Guiducci, S. et al. Bone marrow–derived mesenchymal stem cells from early diffuse systemic sclerosis exhibit a paracrine machinery and stimulate angiogenesis in vitro. Ann. Rheum. Dis. 70, 2011–2021 (2011).

    Article  CAS  PubMed  Google Scholar 

  49. Kasper, G. et al. Mesenchymal stem cells regulate angiogenesis according to their mechanical environment. Stem Cells 25, 903–910 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Li, B. & Aspden, R.M. Mechanical and material properties of the subchondral bone plate from the femoral head of patients with osteoarthritis or osteoporosis. Ann. Rheum. Dis. 56, 247–254 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Goldring, S.R. Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Ther. Adv. Musculoskelet. Dis. 4, 249–258 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Goldring, S.R. Role of bone in osteoarthritis pathogenesis. Med. Clin. North Am. 93, 25–35 (2009).

    Article  PubMed  Google Scholar 

  53. Goldring, M.B. & Goldring, S.R. Osteoarthritis. J. Cell. Physiol. 213, 626–634 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Chytil, A., Magnuson, M.A., Wright, C.V. & Moses, H.L. Conditional inactivation of the TGF-β type II receptor using Cre:Lox. Genesis 32, 73–75 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Qiu, T. et al. TGF-β type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat. Cell Biol. 12, 224–234 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jones, M.D. et al. In vivo microfocal computed tomography and micro-magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat. Arthritis Rheum. 62, 2726–2735 (2010).

    Article  PubMed  Google Scholar 

  57. Lee, J.H. et al. Subchondral fluid dynamics in a model of osteoarthritis: use of dynamic contrast-enhanced magnetic resonance imaging. Osteoarthritis Cartilage 17, 1350–1355 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wu, X. et al. Inhibition of Sca-1–positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling. Cell Stem Cell 7, 571–580 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cao, X. et al. Irradiation induces bone injury by damaging bone marrow microenvironment for stem cells. Proc. Natl. Acad. Sci. USA 108, 1609–1614 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Angeby-Möller, K., Berge, O.G. & Hamers, F.P. Using the CatWalk method to assess weight-bearing and pain behaviour in walking rats with ankle joint monoarthritis induced by carrageenan: effects of morphine and rofecoxib. J. Neurosci. Methods 174, 1–9 (2008).

    Article  PubMed  CAS  Google Scholar 

  61. Hamers, F.P., Koopmans, G.C. & Joosten, E.A. CatWalk-assisted gait analysis in the assessment of spinal cord injury. J. Neurotrauma 23, 537–548 (2006).

    Article  PubMed  Google Scholar 

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Acknowledgements

This research was supported by US National Institutes of Health grants DK 057501 and DK 08098 (both to X.C.). We thank R. Luck and L. Sakowski for collecting samples.

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G.Z. conceived the ideas for experimental designs, conducted the majority of the experiments, analyzed data and prepared the manuscript. C.W. conducted some of the surgery, performed MRI and μCT analyses and helped with manuscript preparation. X.J. provide ideas and helped with behavior analysis. Y.L. conduced cell culture, western blot and behavior analysis and helped with manuscript preparation. J.L.C., W.C. and M.W. helped compose the manuscript. S.C.M., F.B.A., F.J.F., A.C. and P.S. provided human specimens. D.A. and J.A.C. helped with MRI analysis. J.Y. performed computerized simulation. Q.C., X.Z., L.R., Z.Z. and W.W.L. provided suggestions for the project. X.C. developed the concept, supervised the project, conceived the experiments and wrote most of the manuscript.

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Correspondence to Xu Cao.

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Zhen, G., Wen, C., Jia, X. et al. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19, 704–712 (2013). https://doi.org/10.1038/nm.3143

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