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Marian F. Young, Ph.D.

Senior InvestigatorMarian Young, Ph.D.
Research Biologist
Chief, Molecular Biology of Bones and Teeth Section

BETHESDA MD 20892-4320

Phone: (301) 496-8860
E-mail: Dr. Marian F. Young

Biographical Sketch

Marian F. Young is chief of the Molecular Biology of Bones and Teeth Section in the Craniofacial and Skeletal Diseases Branch, NIDCR. She received her B.S. from SUNY at Oneonta, NY (1976), and her Ph.D. in developmental biology from the Department of Genetics and Cell Biology at the University of Connecticut (1981). After a fellowship in the Lab of Developmental Biology and Anomalies at the NIDR (1981-1983), Dr. Young headed a group in the Mineralized Tissue Research Branch (also at the NIDR) where she began her investigations on the molecular biology and function of extracellular matrix (ECM) proteins in skeletal tissues. Her current research focuses on regulation and function of small proteoglycans in mineralized tissues and in their potential role in controlling pathological skeletal conditions such as osteoporosis, osteoarthritis and ectopic ossification. These pathologies originated by defects in stem cells whose fate was shown to be regulated by the ECM.

Dr. Young has published over 190 peer-reviewed articles, reviews and book chapters on the molecular biology of ECM in mineralizing tissue. She has organized several symposia and scientific conferences on the topic of bones and teeth, mineralization and the ECM. In the NIH community she has served on a myriad of committees, some of which she chaired for promotion and tenure action, oversight of animal facilities, and summer student research. Other NIH service includes participation in the graduate partnership program, administrative oversight, and serving as project officer for contracts awarded to the NIDCR. She has supervised dozens of research fellows and students, and considers training of future dental researchers to be a critical role as a senior investigator at the NIDCR.

Research Interests/Scientific Focus

The goal of the Section is to explore the mechanisms that control the function of extracellular matrix proteins found in the skeleton. Our current strategy focuses on a subcategory of matrix components known as small leucine-rich proteoglycans (SLRPs). In the past several years, we have studied the function of three SLRPs, biglycan (bgn) decorin (dcn) and fibromodulin (fmod) and have focused on mechanistic analysis of their unique roles in bones, teeth, cartilage and tendon. Our working hypothesis is that these SLRP’s control skeletal tissue function via both anabolic (through differentiation and formation) and catabolic (breakdown or resorption) mechanisms which, in some cases, work by modulating growth factor availability. Part of our goal was to uncover novel factors that synergize with the SLRPs to control their function. The ultimate purpose of this work is to develop practical applications for these SLRPs in ameliorating diseases such as osteopenia (low bone mass), osteoarthritis (loss of cartilage) and ectopic bone formation in soft tissues.

A brief summary of the major achievements in recent years are listed as follows:

  • An induced model of bone resorption was used to determine that bgn is important in regulating osteolysis. Co-cultures of normal and Bgn-deficient osteoblasts and osteoclasts were used to uncover the cellular basis for increased osteolysis in bgn deficiency. Our data show that increased osteoclastogenesis comes from a defect in the osteoblast that has both decreased differentiation and increased proliferation in the absence of bgn, both of which could modulate osteoclastogenesis and subsequent osteolysis.
  • Micro arrays using mRNA from osteoblasts derived from normal and Bgn-deficient mice were performed and uncovered that the loss of Bgn causes a vast repertoire of mRNA expression patterns to be altered. Some of these data were subsequently used to decipher mechanisms of SLRP action in osteoclast differentiation, cell proliferation, and altered BMP-responsiveness.
  • The overlapping roles of bgn with decorin (dcn) in regulating osteopenia were uncovered by creating mice that are deficient in both Bgn and Dcn. The cellular basis for low bone mass in this model was found to be from over-active TGF-beta 1 signaling that causes osteogenic precursors in bone marrow to undergo pre-mature apoptosis rather than osteogenesis.
  • Craniofacial defects that develop in the combined absence of Bgn and Dcn were uncovered and included impaired posterior frontal suture fusion manifesting with severe hypomineralization of the calvaria. One molecular basis for this abnormality may be from changes in Dlx-5 expression, a transcription factor that was found diminished in the bgn/dcn knockout mice.
  • Bgn and fmod were found to be abundant in the temporomandibular joint (TMJ) leading us to speculate they could control TMJ integrity. Analysis of mice deficient in Bgn and Fmod showed that the mutant TMJ's developed features of classic osteoarthritis (OA) including cell clustering and accellularity caused by increased chondrocyte proliferation and apoptosis respectively. These abnormalities accompanied redistribution of type II collagen and may be the basis for superficial clefting and premature cartilage demise observed in this animal model.
  • Tendons from Bgn/Fmod deficient mice were shown to develop ectopic bones leading to the hypothesis that they harbor progenitor cells sensitive to the composition of the ECM. Using classic protocols, we showed that tendon has a small population cells with stem cell features and showed that in the absence of Fmod and Bgn, these tendon stem/progenitor cells are subject to excess BMP-activity, causing them to form bone instead of tendon.
  • We determined the function of a protein that associates with bgn called Wnt induced secreted protein (WISP-1) in osteogenic cells. Our studies showed that WISP-1 increases proliferation and differentiation in a fashion that works in cooperation with TGF-beta and BMP-2.
  • Bgn was found to bind to key components of the wnt pathway including wnt3a and LRP-6 and modulate their functions. In bone, the modulation of wnt signaling controlled the fate of osteoprogenitor cells both in vitro as well as in vivo. These studies support the concept that bgn could potentially be a new biological agent valuable for therapy of Wnt-related diseases.

Selected Publications

  1. Modulation of canonical Wnt signaling by the extracellular matrix component biglycan. Berendsen AD, Fisher LW, Kilts TM, Owens RT, Robey PG, Gutkind JS, Young MF Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17022-7. Epub 2011 Oct 3.PMID:21969569 [PubMed - in process]
  2. WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity. Ono M, Inkson CA, Kilts TM, Young MF. J Bone Miner Res. 2011 Jan;26(1):193-208. PMID: 20684029 [PubMed - as supplied by publisher]
  3. Biglycan and fibromodulin have essential roles in regulating chondrogenesis and extracellular matrix turnover in temporomandibular joint osteoarthritis. Embree MC, Kilts TM, Ono M, Inkson CA, Syed-Picard F, Karsdal MA, Oldberg A, Bi Y, Young MF. Am J Pathol. 2010 Feb;176(2):812-26. Epub 2009 Dec 24.
  4. TGF-beta1 and WISP-1/CCN-4 can regulate each other's activity to cooperatively control osteoblast function. Inkson CA, Ono M, Kuznetsov SA, Fisher LW, Robey PG, Young MF. J Cell Biochem. 2008 Aug 1;104(5):1865-78.PMID: 18404666 [PubMed - indexed for MEDLINE] Free PMC Article
  5. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF. Nat Med. 2007 Oct;13(10):1219-27. Epub 2007 Sep 9
  6. Impaired posterior frontal sutural fusion in the biglycan/decorin double deficient mice. Wadhwa S, Bi Y, Ortiz AT, Embree MC, Kilts T, Iozzo R, Opperman LA, Young MF. Bone. 2007 Apr;40(4):861-6. Epub 2006 Dec 26.PMID: 17188951 [PubMed - indexed for MEDLINE] Free PMC Article
  7. Biglycan deficiency increases osteoclast differentiation and activity due to defective osteoblasts. Bi Y, Nielsen KL, Kilts TM, Yoon A, A Karsdal M, Wimer HF, Greenfield EM, Heegaard AM, Young MF. Bone. 2006 Jun;38(6):778-86. Epub 2005 Dec 20.PMID: 16364709 [PubMed - indexed for MEDLINE]
  8. Targeted disruption of two small leucine-rich proteoglycans, biglycan and decorin, excerpts divergent effects on enamel and dentin formation. Goldberg M, Septier D, Rapoport O, Iozzo RV, Young MF, Ameye LG. Calcif Tissue Int. 2005 Nov;77(5):297-310. Epub 2005 Nov 5.
  9. Accelerated osteoarthritis in the temporomandibular joint of biglycan/fibromodulin double-deficient mice. Wadhwa S, Embree MC, Kilts T, Young MF, Ameye LG. Osteoarthritis Cartilage. 2005 Sep;13(9):817-27.
  10. Extracellular matrix proteoglycans control the fate of bone marrow stromal cells. Bi Y, Stuelten CH, Kilts T, Wadhwa S, Iozzo RV, Robey PG, Chen XD, Young MF. J Biol Chem. 2005 Aug 26;280(34):30481-9. Epub 2005 Jun 17.PMID: 15964849 [PubMed - indexed for MEDLINE]
  11. The small leucine-rich proteoglycan biglycan modulates BMP-4-induced osteoblast differentiation. Chen XD, Fisher LW, Robey PG, Young MF. FASEB J. 2004 Jun;18(9):948-58.
  12. Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues. Corsi A, Xu T, Chen XD, Boyde A, Liang J, Mankani M, Sommer B, Iozzo RV, Eichstetter I, Robey PG, Bianco P, Young MF. J Bone Miner Res. 2002 Jul;17(7):1180-9.PMID: 12102052 [PubMed - indexed for MEDLINE] Related citations
  13. Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis. Ameye L, Aria D, Jepsen K, Oldberg A, Xu T, Young MF. FASEB J. 2002 May;16(7):673-80.PMID: 11978731 [PubMed - indexed for MEDLINE] Related citations
  14. Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells. Chen XD, Shi S, Xu T, Robey PG, Young MF. J Bone Miner Res. 2002 Feb;17(2):331-40.PMID: 11811564 [PubMed - indexed for MEDLINE]
  15. Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice. Xu T, Bianco P, Fisher LW, Longenecker G, Smith E, Goldstein S, Bonadio J, Boskey A, Heegaard AM, Sommer B, Satomura K, Dominguez P, Zhao C, Kulkarni AB, Robey PG, Young MF. Nat Genet. 1998 Sep;20(1):78-82.PMID: 9731537 [PubMed - indexed for MEDLINE]

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This page last updated: February 26, 2014