Abstract
As the worldwide population grows and life expectancies continue to increase, degenerative diseases of the bones, muscles, and connective tissue are a growing problem for society. Current therapies for osteodegenerative disorders such as hormone replacement therapies, calcium/vitamin D supplements and oral bisphosphonates are often inadequate to stop degeneration and/or have serious negative side effects. Thus, there is an urgent need in the medical community for more effective and safer treatments. Stem cell therapies for osteodegenerative disorders have been rigorously explored over the last decade and are yielding some promising results in animal models and clinical trials. Although much work still needs to be done to ensure the safety and efficacy of these therapies, stem cells represent a new frontier of exciting possibilities for bone and cartilage regeneration.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Embryonic stem cell therapy for osteo-degenerative disorders. Biotechnol. Interact. 17, 8–14 (2005). •• Excellent reference for using stem cells to study osteodegenerative diseases.
- 2 . Bone Health and Osteoporosis: a Report of the Surgeon General. Reports of the Surgeon General, MD, USA (2004 ).
- 3 . WHO Technical Report: Assessment of Osteoporosis at the Primary Health-care Level. WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK, 66 (2007).
- 4 Why do geriatric outpatients have so many moderate and severe vertebral fractures? Exploring prevalence and risk factors. Age Ageing 41(2), 200–206 (2012).
- 5 . Revision hip replacement in patients 55 years of age and younger. Hip Int. 23(2), 162–165 (2013).
- 6 Expression of estrogen receptors (α, β) and insulin-like growth factor-I in breast tissue from surgically postmenopausal cynomolgus macaques after long-term treatment with HRT and tamoxifen. Breast 11(4), 295–300 (2002).
- 7 Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am. J. Med. 126(1), 13–20 (2013).
- 8 . Bisphosphonate-related osteonecrosis of the jaws. A severe side effect of bisphosphonate therapy. Acta Medica (Hradec Kralove) 55, 111–115 (2012).
- 9 Peripheral-blood stem cells versus bone marrow from unrelated donors. N. Engl. J. Med. 367(16), 1487–1496 (2012).
- 10 Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).
- 11 . The potential of muscle stem cells. Dev. Cell 1, 333–342 (2001).
- 12 . Differentiation of human adispose tissue using extracts of rat cardiomyocytes. Biophys. Biochem. Res. Commun. 314, 420–427 (2003).
- 13 Protocols for obtainment and isolation of two mesenchymal stem cell sources in sheep. Acta Cir. Bras. 26(4), 267–273 (2011).
- 14 . Isolation and characterization of human mesenchymal stem cells derived from shoulder tissues. Am. J. Sport Med. 41, 657–668 (2013).
- 15 . Concise review: the periosteum: tapping into a reservoir of clinically useful progenitor cells. Stem Cells Transl. Med. 1, 480–491 (2012).
- 16 . Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).
- 17 . Dormant and restless skin stem cells. Nature 489, 215–217 (2012).
- 18 . Adult human gingival epithelial cells as a source for whole tooth bioengineering. J. Dent. Res. 92, 329–334 (2013).
- 19 . Stem cells and neurological diseases. Cell Prolif. 41, 94–114 (2008).
- 20 . Stem cells in clinical practice: applications and warnings. J. Exp. Clin. Cancer Res. 30, 9–29 (2011). • Useful insight into both the potential and risk of using embryonic stem cells (ESCs) for therapeutics.
- 21 . The stem cell movement. Circ. Res. 102, 1155–1168 (2008).
- 22 . Repair of articular cartilage defects using mesenchymal stem cells. Tissue Eng. 1(1), 345–353 (1995).
- 23 . Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Engl. J. Med. 331, 889–895 (1994).
- 24 A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J. Bone Joint Surg. Am. 89, 2105 (2007).
- 25 Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J. Tissue Eng. Regen. Med. 5(2), 146–150 (2011).
- 26 . Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc. Natl Acad. Sci. USA 94, 5320–5325 (1997).
- 27 Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).
- 28 . Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum. 46(3), 704–713 (2002).
- 29 Chondrogenic differentiation in femoral bone marrow-derived mesenchymal cells (MSC) from elderly patients suffering osteoarthritis or femoral fracture. Arch. Gerontol. Geriat. 52, 239–242 (2011).
- 30 A comparative assessment of cartilage and joint fat pad as a potential source of cells for autologous therapy development in knee osteoarthritis. Rheumatology 46, 1676–1683 (2007).
- 31 Chondrogenic potential of mesenchymal stem cells from patients with rheumatoid arthritis and osteoarthritis: measurements in a microculture system. Cells Tissues Organs 189, 307–316 (2009).
- 32 Treatment of osteoarthritis with infrapatellar fat pad derived mesenchymal stem cells in rabbit. Knee 18, 71–75 (2011).
- 33 Intra-articular delivery of purified mesenchymal stem cells from C57BL/6 or MRL/MpJ superhealer mice prevents post-traumatic arthritis. Cell Transplant. 22(8), 1395–1408 (2012).
- 34 . Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 19, 902–907 (2012).
- 35 Mesenchymal stem cell injections improve knee osteoarthritis. Arthroscopy 29(4), 748–755 (2013).
- 36 NIH Clinical Trials Database. www.clinicaltrials.gov
- 37 Osteoarthritis and you. www.cdc.gov/features/osteoarthritisplan
- 38 Forecasting the burden of advanced knee osteoarthritis over a 20 year period in a cohort of older US adults: impact of obesity Presented at: American College of Rheumatology Annual Scientific Meeting, San Francisco, CA, USA, 25–29 October 2008 (Astract 204).
- 39 . Obesity short circuits stemness gene network in human adipose multipotent stem cells. FASEB J. 25, 4111–4126 (2011).
- 40 . Diet-induced obesity alters the differentiation potential of stem cells isolated from bone marrow, adipose tissue and infrapatellar fad pad: the effects of free fatty acids. Int. J. Obes. (Lond.) 37(8), 1079–1087 (2012).
- 41 . Catabolic factors and osteoarthritis conditioned medium inhibit chondrogenesis of human mesenchymal stem cells. Tissue Eng. 18(1–2), 45–54 (2012).
- 42 . Regulation of aggrecanases from the ADAMTS family and aggrecan neoepitope formation during in vitro chondrogenesis of human mesenchymal stem cells. Eur. Cells Mater. 23, 320–332 (2012).
- 43 Human umbilical cord blood-derived CD34+ cells reverse osteoporosis in NOD/SCID mice by altering osteoblastic and osteoclastic activities. PLoS ONE 7(6), e39365 (2012).
- 44 Long-term functional engraftment of mesenchymal progenitor cells in a mouse model of accelerated aging. Stem Cells 31(3), 607–611 (2013).
- 45 Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat. Med. 18(3), 456–462 (2012).
- 46 . Beneficial effects of non-matched allogeneic cord blood mononuclear cells upon patients with idiopathic osteoporosis. J. Transl. Med. 10, 102–107 (2012).
- 47 . Mesenchymal stem cells and the treatment of conditions and diseases: the less glittering side of a conspicuous stem cell for basic research. Stem Cells Dev. 22, 193–203 (2013).
- 48 Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS ONE 3, e2213 (2008).
- 49 Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells. BMC Cell Biol. 9, 60 (2008).
- 50 . The production and directed differentiation of human embryonic stem cells. Endocr. Rev. 27, 208–219 (2006).
- 51 . Derivation and maintenance of embryonic stem cell cultures. Methods Mol. Biol. 75, 173–184 (1997).
- 52 Embryonic stem cell lines derived from human blastocysts. Science 5391(282), 1145–1147 (1998).
- 53 . Transcriptional regulation of nanog by OCT4 and SOX2. J. Biol. Chem. 280(26), 24731–24737 (2005).
- 54 . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4), 663–676 (2006).
- 55 Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5), 861–872 (2007).
- 56 Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat. Biotechnol. 26, 795–797 (2008).
- 57 Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341(6146), 651–654 (2013).
- 58 . Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 27(11), 2667–2774 (2009).
- 59 Simple and efficient method for generation of induced pluripotent stem cells using piggyBac transposition of doxycycline-inducible factors and an EOS reporter system. Genes Cells 16(7), 815–825 (2011).
- 60 Generation of induced pluripotent stem cells from human foetal fibroblasts using the Sleeping Beauty transposon gene delivery system. Differentiation 86(1–2), 30–37 (2013).
- 61 A chemical platform for improved induction of human iPSCs. Nat. Methods 6(11), 805–808 (2009).
- 62 MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells. Nat. Struct. Mol. Biol. 20(10), 1227–1235 (2013).
- 63 . Novel insights into disease modeling using induced pluripotent stem cells. Biol. Pharm. Bull. 36(2), 182–188 (2013). • Thoroughly compiles the various potentials for induced pluripotent stem cells in therapeutics, highlighting the great potential effective drug treatment on a patient-specific basis.
- 64 Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat. Biotechnol. 28, 848–855 (2010). • Highlights one of the main problems in using induced pluripotent stem cells.
- 65 Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).
- 66 Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat. Biotechnol. 29, 1117–1119 (2011).
- 67 Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl Acad. Sci. USA 107, 4335–4340 (2010).
- 68 Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8(2), 228–240 (2011).
- 69 A comparative study of induced pluripotent stem cells generated from frozen, stocked bone marrow- and adipose tissue-derived mesenchymal stem cells. J. Tissue Eng. Regen. Med. 6, 261–271 (2012).
- 70 . Derivation of murine induced pluripotent stem cells (iPS) and assessment of their differentiation toward osteogenic lineage. J. Cell. Biochem. 109, 643–652 (2010).
- 71 Genetically matched human iPS cells reveal that propensity for cartilage and bone differentiation differs with clones, not cell type of origin. PLoS ONE 8(1), e53771 (2013).
- 72 . Reprogramming of mesenchymal stem cells derived from iPSCs seeded on biofunctionalized calcium phosphate scaffold for bone engineering. Biomaterials 4(32), 7862–7872 (2013).
- 73 Efficient commitment to functional CD34+ progenitor cells from human bone marrow mesenchymal stem-cell-derived induced pluripotent stem cells. PLoS ONE 7(4), e34321 (2012).
- 74 . Concise review: induced pluripotent stem cell-derived mesenchymal stem cells: progress toward safe clinical products. Stem Cells 30(1), 42–47 (2013).
- 75 . Make no bones about it: cells could soon be reprogrammed to grow replacement bones? Expert Opin. Biol. Ther. 14(1), 1–5 (2013).
- 76 . Hematopoietic defects and iPSC disease modeling: lessons learned. Immunol. Lett. 155(1–2), 18–20 (2013).
- 77 . Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).
- 78 . Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl Acad. Sci. USA 78(12), 7634–7638 (1981).
- 79 . Geron gets green light for human trial of ES cell-derived product. Nat. Biotechnol. 27, 213–214 (2009).
- 80 . Stem cells were God’s will, says first recipient of treatment. Washington Post, 15th April (2011).
- 81 . Evaluating the first-in-human clinical trial of a human embryonic stem cell-based therapy. Kennedy Inst. Ethics J. 22(3), 243–261 (2012).
- 82 Embryonic stem cell trials for macular degeneration: preliminary report. Lancet 379(9817), 713–720 (2012).
- 83 Advanced Cell Technology. www.advancedcell.com
- 84 . In vitro differentiation of embryonic stem cells into mineralized osteoblasts. Differentiation 17, 18–27 (2003).•• Highlights the promise of using ESCs to regenerate bone.
- 85 . Embryonic stem cell therapy for osteo-degenerative disorders. Biotechnol. Interactions 17, 8–14 (2005).
- 86 . Development of osteoclasts from embryonic stem cells through a pathway that is c-fms but not c-kit dependent. Blood 90(9), 3516–3523 (1997).
- 87 . Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J. Clin. Invest. 115(12), 3318–3325 (2005).
- 88 . Osteoarthritis: detection, pathophysiology, and current/future treatment strategies. Orthop. Nurs. 32(1), 25–36 (2013).
- 89 . Embryonic stem cells for osteo-degenerative diseases. Methods Mol. Biol. 690, 1–30 (2011). •• Provides an excellent source of current protocols and research on ESC use for osteodegenerative disorders.
- 90 . Hyperglycemia impairs skeletogenesis from embryonic stem cells by affecting osteoblast and osteoclast differentiation. Stem Cells Dev. 20, 465–474 (2011).
- 91 . Functions of the TGF-β superfamily in human embryonic stem cells. APMIS 113, 773–789 (2005).
- 92 . IGF-II promotes mesoderm formation. Dev. Biol. 227, 133–145 (2000).
- 93 . Microwell mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11. Proc. Natl Acad. Sci. USA 106, 16978–16983 (2009).
- 94 . From fertilization to gastrulation: axis formation in the mouse embryo. Curr. Opin. Genet. Dev. 11, 384–392 (2001).
- 95 . Osteogenesis from pluripotent stem cells: neural crest or mesodermal origin? In: Embryonic Stem Cells – Differentiation and Pluripotent Alternatives, Kallos MS (Ed). InTech, Rijeka, Croatia, 323–348 (2011).
- 96 . Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells. J. Biosci. Bioeng. 103(5), 389–398 (2007).
- 97 Differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. Mol. Med. 6, 88–95 (2000).
- 98 Differentiation of osteoblasts and in vitro bone formation from murine embryonic stem cells. Tissue Eng. 7, 89–99 (2001).
- 99 . Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors. Bone 36, 758–769 (2005).
- 100 . Osteogenic nodule formation from single embryonic stem cell-derived progenitors. Stem Cell Dev. 15, 865–879 (2006).
- 101 . Enhanced derivation of osteogenic cells from murine embryonic stem cells after treatment with ionic dissolution products of 58 S bioactive sol-gel glass. Tissue Eng. 11, 479–488 (2005).
- 102 . In vitro differentiation of embryonic stem cells into mineralized osteoblasts. Differentiation 17, 18–27 (2003).
- 103 . Leucine-rich amelogenic peptide induces osteogenesis by activation of the Wnt pathway. Biochem. Biophys. Res. Commun. 387, 558–563 (2009).
- 104 . Phenotypic characterization, osteogenic differentiation, and bone regeneration capacity of human embryonic stem cell-derived mesenchymal stem cells. Stem Cell Dev. 18, 1–14 (2009).
- 105 . Formation of a primitive ectoderm like cell population, EPL cells, from ES cells in response to biologically derived factors. J. Cell Sci. 112, 601–612 (1999).
- 106 Cardiomyocyte differentiation of mouse and human embryonic stem cells. J. Anat. 200, 233–242 (2002).
- 107 . Enhanced derivation of osteogenic cells from murine embryonic stem cells after treatment with HepG2-conditioned medium and modulation of the embryoid body formation period: application to skeletal tissue engineering. Tissue Eng. 12, 1381–1392 (2006).
- 108 Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Nat. Biotechnol. 25(12), 1468–1475 (2007).
- 109 Comparison of osteogenesis of human embryonic stem cells within 2D and 3D culture systems. Scand. J. Clin. Lab. Invest. 68, 58–67 (2008).
- 110 . Osteogenic differentiation of mouse embryonic stem cells and mouse embryonic fibroblasts in a three-dimensional self-assembling peptide scaffold. Tissue Eng. 12, 2215–2227 (2006).
- 111 In vivo bone formation from human embryonic stem cell-derived osteogenic cells in poly (D,L-lactic-co-glycolic acid)/hydroxyapatite composite scaffold. Biomaterials 29, 1043–1053 (2008).
- 112 . Stem cell research: toward greater unity in Europe? Cell 139, 649–651 (2009).
- 113 . Stem cell research policies around the world. Yale J. Biol. Med. 82(3), 113–115 (2009).
- 114 . The business of exploiting induced pluripotent stem cells. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 2323–2328 (2011).
- 115 HeinOnline: World’s Largest Image-Based Legal Research Database. http://heinonline.org
- 116 Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. Trends Mol. Med. 6(2), e1000029 (2009).
- 117 . Mutation rate in stem cells: an underestimated barrier on the way to therapy. Trends Mol. Med. 19(5), 273–280 (2013).
- 118 Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63–67 (2011).
- 119 . Supralethal whole body irradiation and isologous bone marrow transplantation in man. J. Clin. Invest. 38, 1709–1716 (1959).
- 120 Development of a human extracellular matrix for applications related with stem cells and tissue engineering. Stem Cell Rev. 8(1), 170–183 (2012).