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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hootman, J.M. & Helmick, C.G. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum. 54, 226–229 (2006).
van den Berg, W.B. Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthritis Cartilage 19, 338–341 (2011).
Berenbaum, F. Osteoarthritis year 2010 in review: pharmacological therapies. Osteoarthritis Cartilage 19, 361–365 (2011).
Hawker, G.A., Mian, S., Bednis, K. & Stanaitis, I. Osteoarthritis year 2010 in review: non-pharmacologic therapy. Osteoarthritis Cartilage 19, 366–374 (2011).
Saito, T. et al. Transcriptional regulation of endochondral ossification by HIF-2α during skeletal growth and osteoarthritis development. Nat. Med. 16, 678–686 (2010).
Yang, S. et al. Hypoxia-inducible factor-2α is a catabolic regulator of osteoarthritic cartilage destruction. Nat. Med. 16, 687–693 (2010).
Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674–1679 (2011).
Glasson, S.S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).
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).
Lories, R.J. & Luyten, F.P. The bone-cartilage unit in osteoarthritis. Nat. Rev. Rheumatol. 7, 43–49 (2011).
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).
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).
Stein, V. et al. Pattern of joint damage in persons with knee osteoarthritis and concomitant ACL tears. Rheumatol. Int. 32, 1197–1208 (2012).
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).
Hill, C.L. et al. Cruciate ligament integrity in osteoarthritis of the knee. Arthritis Rheum. 52, 794–799 (2005).
Suri, S. & Walsh, D.A. Osteochondral alterations in osteoarthritis. Bone 51, 204–211 (2012).
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).
Dreier, R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res. Ther. 12, 216 (2010).
Tchetina, E.V. Developmental mechanisms in articular cartilage degradation in osteoarthritis. Arthritis 2011, 683970 (2011).
Blaney Davidson, E.N., van der Kraan, P.M. & van den Berg, W.B. TGF-β and osteoarthritis. Osteoarthritis Cartilage 15, 597–604 (2007).
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).
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).
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).
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).
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).
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).
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).
Tang, Y. et al. TGF-β1–induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med. 15, 757–765 (2009).
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).
Pritzker, K.P. et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage 14, 13–29 (2006).
Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011).
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).
Lotz, M. Osteoarthritis year 2011 in review: biology. Osteoarthritis Cartilage 20, 192–196 (2012).
Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).
Wiese, C. et al. Nestin expression—a property of multi-lineage progenitor cells? Cell Mol. Life Sci. 61, 2510–2522 (2004).
Kamekura, S. et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13, 632–641 (2005).
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).
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).
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).
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).
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).
Zhang, M. et al. Smad3 prevents β-catenin degradation and facilitates β-catenin nuclear translocation in chondrocytes. J. Biol. Chem. 285, 8703–8710 (2010).
Li, T.F. et al. Smad3-deficient chondrocytes have enhanced BMP signaling and accelerated differentiation. J. Bone Miner. Res. 21, 4–16 (2006).
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).
Koyama, N. et al. Pluripotency of mesenchymal cells derived from synovial fluid in patients with temporomandibular joint disorder. Life Sci. 89, 741–747 (2011).
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).
Cunha, S.I. & Pietras, K. ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood 117, 6999–7006 (2011).
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).
Kasper, G. et al. Mesenchymal stem cells regulate angiogenesis according to their mechanical environment. Stem Cells 25, 903–910 (2007).
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).
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).
Goldring, S.R. Role of bone in osteoarthritis pathogenesis. Med. Clin. North Am. 93, 25–35 (2009).
Goldring, M.B. & Goldring, S.R. Osteoarthritis. J. Cell. Physiol. 213, 626–634 (2007).
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).
Qiu, T. et al. TGF-β type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat. Cell Biol. 12, 224–234 (2010).
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).
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).
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).
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).
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).
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).
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 (PDF 9080 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.3143
This article is cited by
-
Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice
BMC Oral Health (2024)
-
The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease
Cell Research (2024)
-
The emerging studies on mesenchymal progenitors in the long bone
Cell & Bioscience (2023)
-
Re-thinking osteoarthritis pathogenesis: what can we learn (and what do we need to unlearn) from mouse models about the mechanisms involved in disease development
Arthritis Research & Therapy (2023)
-
Effects of genus Epimedium in the treatment of osteoarthritis and relevant signaling pathways
Chinese Medicine (2023)