Most of the bones in the vertebrate skeleton arise from a cartilage template during embryogenesis. This process, known as endochondral ossification, begins with the differentiation of condensed mesenchymal stem cells (MSCs) into chondroprogenitors (immature cartilage cells) and osteoprogenitors (immature bone cells). Both the chondroprogenitor and osteoprogenitor cells undergo a coupled proliferation and differentiation program ultimately leading to the formation of mature cartilage and bone. Various genetic studies have demonstrated that Ihh, Pthrp, BMPs, FGFs, and canonical Wnt signaling pathways are required at multiple stages of normal cartilage and bone development. Deregulation of these signaling circuits during development are a primary cause for a variety of skeletal dysplasias, as well as, age related cartilage and bone pathologies.
A long-term interest of the Hilton lab is to uncover the molecular circuitry regulating lineage commitment, proliferation, and differentiation of MSCs and maturing chondrocytes. My laboratory uses genetic mouse models and primary cell culture techniques coupled with biochemistry to answer questions regarding MSC self-renewal/differentiation, chondrogenesis, and chondrocyte maturation. Recently my lab has generated novel data from a variety of Notch gain and loss-of-function mutant mice demonstrating that Notch signaling pathway suppresses MSC differentiation and plays critical roles in regulating chondrogenesis and chondrocyte maturation. We are currently investigating the exact Notch signaling mechanisms regulating both early and late stages of these processes, as well as, determining how Notch components interact with other known signaling pathways during cartilage development and maintenance. These studies are also being extended to aid in our mechanistic understanding of both fracture repair and osteoarthritis.
Finally, the Hilton lab is continuing to investigate the molecular mechanisms responsible for a developmental bone and cartilage disorder known as Multiple Hereditary Exostoses (MHE). MHE is an autosomal dominant disease caused by mutations in either the Ext1 or Ext2 genes, subunits of the heparan sulphate co-polymerase complex. Affected individuals are diagnosed with cartilaginous bony outgrowths (exostoses) adjacent to the growth plates of endochondral bones, bowing of some bones, and short stature. Although previous studies have shown that defects in Ext1 and Ext2 lead to reduced synthesis and shortened heparan sulphate chains on cell surface proteoglycans, the exact molecular mechanisms underlying this skeletal disease are still unknown. My lab is currently examining various Ext1 conditional mutant mouse models to determine the precise cell lineage and cause of exostosis formation. Additional genetic studies are also aimed at determining the effect that loss of Ext1 function has on specific signaling pathways important during chondrocyte and osteoblast development.

• Dao DY, Jonason JH, Zhang Y, Hsu W, Chen D, Hilton MJ, O'Keefe RJ. Cartilage-specific ß-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. J Bone Miner Res. 2012 Aug; 27(8):1680-94.
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• Kim KO, Sampson ER, Maynard RD, O'Keefe RJ, Chen D, Drissi H, Rosier RN, Hilton MJ, Zuscik MJ. Ski inhibits TGF-ß/phospho-Smad3 signaling and accelerates hypertrophic differentiation in chondrocytes. J Cell Biochem. 2012 Jun; 113(6):2156-66.
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• Kohn A, Dong Y, Mirando AJ, Jesse AM, Honjo T, Zuscik MJ, O'Keefe RJ, Hilton MJ. Cartilage-specific RBPj?-dependent and -independent Notch signals regulate cartilage and bone development. Development. 2012 Mar; 139(6):1198-212.
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• Shu B, Zhang M, Xie R, Wang M, Jin H, Hou W, Tang D, Harris SE, Mishina Y, O'Keefe RJ, Hilton MJ, Wang Y, Chen D. BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development. J Cell Sci. 2011 Oct 15; 124(Pt 20):3428-40.
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• Sampson ER, Hilton MJ, Tian Y, Chen D, Schwarz EM, Mooney RA, Bukata SV, O'Keefe RJ, Awad H, Puzas JE, Rosier RN, Zuscik MJ. Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med. 2011 Sep 21; 3(101):101ra93.
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• Papuga MO, Kwok E, You Z, Rubery PT, Dougherty PE, Pryhuber G, Beck CA, Hilton MJ, Awad HA, Schwarz EM. TNF is required for the induction but not the maintenance of compression-induced BME signals in murine tail vertebrae: limitations of anti-TNF therapy for degenerative disc disease. J Orthop Res. 2011 Sep; 29(9):1367-74.
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• Sampson ER, Beck CA, Ketz J, Canary KL, Hilton MJ, Awad H, Schwarz EM, Chen D, O'Keefe RJ, Rosier RN, Zuscik MJ. Establishment of an index with increased sensitivity for assessing murine arthritis. J Orthop Res. 2011 Aug; 29(8):1145-51.
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• Katzel EB, Wolenski M, Loiselle AE, Basile P, Flick LM, Langstein HN, Hilton MJ, Awad HA, Hammert WC, O'Keefe RJ. Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing. J Orthop Res. 2011 May; 29(5):684-93.
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• Papuga MO, Proulx ST, Kwok E, You Z, Rubery PT, Dougherty PE, Hilton MJ, Awad HA, Schwarz EM. Chronic axial compression of the mouse tail segment induces MRI bone marrow edema changes that correlate with increased marrow vasculature and cellularity. J Orthop Res. 2010 Sep; 28(9):1220-8.
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• Gunnell LM, Jonason JH, Loiselle AE, Kohn A, Schwarz EM, Hilton MJ, O'Keefe RJ. TAK1 regulates cartilage and joint development via the MAPK and BMP signaling pathways. J Bone Miner Res. 2010 Aug; 25(8):1784-97.
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• Dong Y, Jesse AM, Kohn A, Gunnell LM, Honjo T, Zuscik MJ, O'Keefe RJ, Hilton MJ. RBPjkappa-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development. Development. 2010 May; 137(9):1461-71.
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• Dao DY, Yang X, Flick LM, Chen D, Hilton MJ, O'Keefe RJ. Axin2 regulates chondrocyte maturation and axial skeletal development. J Orthop Res. 2010 Jan; 28(1):89-95.
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• Crane DP, Gromov K, Li D, Søballe K, Wahnes C, Büchner H, Hilton MJ, O'Keefe RJ, Murray CK, Schwarz EM. Efficacy of colistin-impregnated beads to prevent multidrug-resistant A. baumannii implant-associated osteomyelitis. J Orthop Res. 2009 Aug; 27(8):1008-15.
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• Metcalf JA, Zhang Y, Hilton MJ, Long F, Ponder KP. Mechanism of shortened bones in mucopolysaccharidosis VII. Mol Genet Metab. 2009 Jul; 97(3):202-11.
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• Christopher MJ, Liu F, Hilton MJ, Long F, Link DC. Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood. 2009 Aug 13; 114(7):1331-9.
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• Yin Y, White AC, Huh SH, Hilton MJ, Kanazawa H, Long F, Ornitz DM. An FGF-WNT gene regulatory network controls lung mesenchyme development. Dev Biol. 2008 Jul 15; 319(2):426-36.
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• Wu X, Tu X, Joeng KS, Hilton MJ, Williams DA, Long F. Rac1 activation controls nuclear localization of beta-catenin during canonical Wnt signaling. Cell. 2008 Apr 18; 133(2):340-53.
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• Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, Kronenberg HM, Teitelbaum SL, Ross FP, Kopan R, Long F. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008 Mar; 14(3):306-14.
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• Zuscik MJ, Hilton MJ, Zhang X, Chen D, O'Keefe RJ. Regulation of chondrogenesis and chondrocyte differentiation by stress. J Clin Invest. 2008 Feb; 118(2):429-38.
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• Bai S, Kopan R, Zou W, Hilton MJ, Ong CT, Long F, Ross FP, Teitelbaum SL. NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem. 2008 Mar 7; 283(10):6509-18.
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• Hilton MJ, Tu X, Long F. Tamoxifen-inducible gene deletion reveals a distinct cell type associated with trabecular bone, and direct regulation of PTHrP expression and chondrocyte morphology by Ihh in growth region cartilage. Dev Biol. 2007 Aug 1; 308(1):93-105.
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• Hilton MJ, Tu X, Cook J, Hu H, Long F. Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Development. 2005 Oct; 132(19):4339-51.
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• Hilton MJ, Gutiérrez L, Martinez DA, Wells DE. EXT1 regulates chondrocyte proliferation and differentiation during endochondral bone development. Bone. 2005 Mar; 36(3):379-86.
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• Hu H, Hilton MJ, Tu X, Yu K, Ornitz DM, Long F. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development. 2005 Jan; 132(1):49-60.
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• Hilton MJ, Sawyer JM, Gutiérrez L, Hogart A, Kung TC, Wells DE. Analysis of novel and recurrent mutations responsible for the tricho-rhino-phalangeal syndromes. J Hum Genet. 2002; 47(3):103-6.
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• Hilton MJ, Gutiérrez L, Zhang L, Moreno PA, Reddy M, Brown N, Tan Y, Hill A, Wells DE. An integrated physical map of 8q22-q24: use in positional cloning and deletion analysis of Langer-Giedion syndrome. Genomics. 2001 Jan 15; 71(2):192-9.
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• Olgiate J, Ehmann GL, Vidyarthi S, Hilton MJ, Bachenheimer SL. Herpes simplex virus induces intracellular redistribution of E2F4 and accumulation of E2F pocket protein complexes. Virology. 1999 Jun 5; 258(2):257-70.
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