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History

The Odgren lab began as, and has evolved from, that of Sandy C. Marks, Jr. D.D.S., Ph.D. Sandy was a founding faculty member of the UMass Chan Medical School who taught anatomy to the first 32 consecutive classes of entering medical students. He was Professor of Cell Biology, Radiology, and Surgery. Sandy was a truly gifted and much beloved scientist, surgeon, scholar, teacher, editor, author, and humanitarian who accomplished great things in many areas of his extraordinary life; but his particular research specialty was osteopetrotic models in mice and rats. You may read more about Sandy’s remarkable life and achievements here.

When Sandy passed away suddenly in 2002, Paul Odgren took over as PI of the lab. Our main interest has been in osteoclast biology and through that, the regulation of bone metabolism. A great deal of our work has utilized mouse and rat strains which carry mutations that prevent normal bone resorption by osteoclasts. This leads to a condition called osteopetrosis, which in some ways is the opposite of osteoporosis in that it leads to too much bone. Identification of the mutations responsible along with gene expression screens have led to a series of publications describing novel genes and/or genes not previously known to be important in skeletal metabolism in general or osteoclast biology in particular.

We have several active collaborations, including with the lab of Dr. Wim Van Hul of the University of Antwerp, Belgium; Drs. Fraser Coxon and Miep Helfrich of the University of Aberdeen, UK; Dr. Ivan Dikic of the University of Frankfurt, Germany; Dr. Riccardo Battaglino, the Forsyth Institute of Dental Medicine, Cambridge, MA; Drs. Steven Popoff and Fayez Safadi, Temple U. School of Medicine, Philadelphia; and Dr. Leah Rae Donahue of The Jackson Laboratory, Bar Harbor, ME.

Our current projects are focused 1) on a protein called plekhm1 which causes osteopetrosis in the incisors absent (ia) rat strain and in humans with a truncation mutation, 2) on mapping the causative mutation in the osteopetrosis (op) rat strain, 3) on producing a plekhm1 gain-of-function mouse model, d) on vesicle trafficking and ruffled border formation in osteoclasts, and 4) on the mechanisms of pre-osteoclast fusion.

Current and recent grant-funded projects have included:

  • Mapping the osteopetrotic mutations in the tl, ia, and op strains of rat (in collaboration with the Van Hul lab, U. Antwerp)
  • Exploring the role of connective tissue growth factor in bone metabolism (in collaboration with the Popoff lab) 
  • In situ hybridization to study gene expression in normal and mutant skeletal tissues
  • Identification and characterization of craniofacial mutations in the mouse (in collaboration with the Donahue lab, The Jackson Laboratory)
  • Investigating TRANCE/RANKL in osteoclast biology (in collaboration with the Y. Choi lab, U. Penn)
  • Gene discovery through microarray analysis of differentiating osteoclasts
  • Growth plate dysplasia in osteopetrotic models
  • plekhm1 in osteoclast biology and vesicle trafficking (in collaboration with the Van Hul, Coxon, Helfrich and Dikic labs)

A summary of some of our research contributions over the past decade:

  • Showed that deficient vitamin D binding protein-macrophage activating factor is NOT a universal feature of osteopetrosis, as had been previously reported (Odgren et al., 1999)
  • Demonstrated abnormalities in collagen gene expression in both intramembranous and endochondral bone formation in craniofacial and other skeletal tissues with growth defects (Marks et al., 2000; Marks et al., 1999a)
  • Discovered novel roles for connective tissue growth factor in osteoblast differentiation and bone formation (Safadi et al., 2003; Xu et al., 2000)
  • Demonstrated in vivo the need for local delivery of RANKL (TRANCE) to regulate normal bone growth and tooth eruption (Kim et al., 2000; Odgren et al., 2003b)
  • Reported an improved method for generating high-activity non-radioactive probes for in situ hybridization in tissues (Odgren et al., 2003a)
  • Discovered the genetic cause of osteopetrosis in 2 naturally occurring rat models, toothless, and incisors absent. Found one of those genes (Plekhm1) to be the cause of bone disease in humans (Odgren et al., 2001; Perdu et al., 2009; Van Wesenbeeck et al., 2007; Van Wesenbeeck et al., 2002; van Wesenbeeck et al., 2004).
  • Developed novel means to measure cartilage dysplasia by digital micrograph analysis (Devraj et al., 2004)
  • Developed an improved method for chondrocyte cryopreservation for in vitro differentiation studies (Gartland et al., 2005)
  • Analyzed expression changes in chemokines and their receptors during pre-osteoclast chemotaxis and differentiation and identified a key role for CCL9 and its receptor, CCR1 in osteoclast differentiation in the skeleton in general and in relation to tooth eruption (Odgren et al., 2006a; Yang et al., 2006b; Yang and Odgren, 2005)
  • Demonstrated that osteoclasts can differentiate in the absence of the “essential” factor, RANKL (TRANCE) (Kim et al., 2005)
  • Showed that the often-used E. coli LacZ (beta-galactosidase) gene is inappropriate for detection of transgene expression in osteoclasts (Odgren et al., 2006b)
  • Demonstrated a key role for bone morphogenetic protein 5 in promoting chondrocyte differentiation and cartilage synthesis in vivo and in vitro (Mailhot et al., 2008)
  • Identified 4 novel genes with important roles in osteoclast fusion, proton sensing, ion transport, and redox regulation (Battaglino et al., 2008; Xu et al., 2010; Yang et al., 2008; Yang et al., 2006a)
  • Presented detailed histochemical and cellular analysis of the invasion of growth cartilage by capillaries in normal and osteopetrotic rats (Gartland et al., 2009)
  • Identified and characterized a novel mutation in Lmna in mice and demonstrated its relevance as a model for human laminopathy syndromes, including progeria (Odgren et al., 2010)
  • Developed a detailed approach to teaching biotechnology at the undergraduate level through the use of gene expression, bioinformatics, and osteoclast differentiation (Birnbaum et al., 2010)
  • Throughout the time covered by this summary, have contributed reviews, chapters, and other scholarly articles on bone research, bone development, bone structure, and osteoclast and chondrocyte biology (Marks et al., 2004; Marks and Odgren, 2002; Marks et al., 1999b; Odgren et al., 2004; Odgren et al., 1997; Odgren and Marks, 1998; Odgren et al., 2003c)

References

Battaglino, R.A., Pham, L., Morse, L.R., Vokes, M., Sharma, A., Odgren, P.R., Yang, M., Sasaki, H., and Stashenko, P. (2008). NHA-oc/NHA2: a mitochondrial cation-proton antiporter selectively expressed in osteoclasts. Bone 42, 180-192.

Birnbaum, M.J., Picco, J., Clements, M., Witwicka, H., Yang, M.H., Hoey, M.T., and Odgren, P.R. (2010). Using Osteoclast Differentiation as a Model for Gene Discovery in an Undergraduate Cell Biology Laboratory. Biochem Mol Biol Edu 38, 385-392.

Devraj, K., Bonassar, L.J., MacKay, C.A., Mason-Savas, A., Gartland, A., and Odgren, P.R. (2004). A new histomorphometric method to assess growth plate chondrodysplasia and its application to the toothless (tl, Csf1null) osteopetrotic rat. Connect Tissue Res 45, 1-10.

Gartland, A., Mason-Savas, A., Yang, M., MacKay, C.A., Birnbaum, M.J., and Odgren, P.R. (2009). Septoclast deficiency accompanies postnatal growth plate chondrodysplasia in the toothless (tl) osteopetrotic, colony-stimulating factor-1 (CSF-1)-deficient rat and is partially responsive to CSF-1 injections. Am J Pathol 175, 2668-2675.

Gartland, A., Mechler, J., Mason-Savas, A., MacKay, C.A., Mailhot, G., Marks, S.C., Jr., and Odgren, P.R. (2005). In vitro chondrocyte differentiation using costochondral chondrocytes as a source of primary rat chondrocyte cultures: an improved isolation and cryopreservation method. Bone 37, 530-544.

Kim, N., Kadono, Y., Takami, M., Lee, J., Lee, S.H., Okada, F., Kim, J.H., Kobayashi, T., Odgren, P.R., Nakano, H., et al. (2005). Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J Exp Med 202, 589-595.

Kim, N., Odgren, P.R., Kim, D.K., Marks, S.C., Jr., and Choi, Y. (2000). Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci U S A 97, 10905-10910.

Mailhot, G., Yang, M., Mason-Savas, A., Mackay, C.A., Leav, I., and Odgren, P.R. (2008). BMP-5 expression increases during chondrocyte differentiation in vivo and in vitro and promotes proliferation and cartilage matrix synthesis in primary chondrocyte cultures. J Cell Physiol 214, 56-64.

Marks, S.C., Jr., Gartland, A., and Odgren, P.R. (2004). Skeletal Development. In Encyclopedia of Endocrine Diseases, L. Martini, ed. (San Diego, Elsevier), pp. 261-272.

Marks, S.C., Jr., Lundmark, C., Christersson, C., Wurtz, T., Odgren, P.R., Seifert, M.F., MacKay, C.A., Mason-Savas, A., and Popoff, S.N. (2000). Endochondral bone formation in toothless (osteopetrotic) rats: failures of chondrocyte patterning and type X collagen expression. Int J Dev Biol 44, 309-316.

Marks, S.C., Jr., Lundmark, C., Wurtz, T., Odgren, P.R., MacKay, C.A., Mason-Savas, A., and Popoff, S.N. (1999a). Facial development and type III collagen RNA expression: concurrent repression in the osteopetrotic (Toothless,tl) rat and rescue after treatment with colony-stimulating factor-1. Dev Dyn 215, 117-125.

Marks, S.C., Jr., and Odgren, P.R. (2002). The structure and development of the skeleton. In Principles of Bone Biology, J.P. Bilezikian, L.G. Raisz, and G.A. Rodan, eds. (New York, Academic Press), pp. 3-15.

Marks, S.C.J., Odgren, P.R., Popoff, S.N., and Wurtz, T. (1999b). Sutures, Growth Plates and the Craniofacial Base - Experimental Studies in the Toothless (tl-Osteopetrotic) Rat. Ann Acad Med Singapore 28, 650-654.

Odgren, P.R., Birnbaum, M.J., Yang, M., Mailhot, G., MacKay, C.A., and Mason-Savas, A. (2006a). Osteopetrotic mutations as tools to study tooth eruption: recent progress in understanding the role of chemokines in osteoclast differentiation in vivo. In Proc 8th International Conference on Biomineralization, Eruption, and Movement of Teeth, Z. Davidovitch, J. Mah, and S. Suthanarak, eds. (Bangkok, U. So. California School of Dentistry), pp. 1-10.

Odgren, P.R., Gartland, A., and MacKay, C.A. (2003a). Production of high-activity digoxigenin-labeled riboprobes for in situ hybridization using the AmpliScribe™ T7 High Yield Transcription Kit. Epicentre Forum 10, 6-7.

Odgren, P.R., Gartland, A., Mason-Savas, A., and Marks, S.C.J. (2004). Bone Structure. In Encyclopedia of Endocrine Diseases, L. Martini, ed. (San Diego, Academic Press), pp. 392-400.

Odgren, P.R., Hermey, D.C., Popoff, S.N., and Marks, S.C., Jr. (1997). Cellular and molecular strategies for studying the regulation of bone resorption using the toothless (osteopetrotic) mutation in the rat. Histol Histopathol 12, 1151-1157.

Odgren, P.R., Kim, N., MacKay, C.A., Mason-Savas, A., Choi, Y., and Marks, S.C., Jr. (2003b). The role of RANKL (TRANCE/TNFSF11), a tumor necrosis factor family member, in skeletal development: effects of gene knockout and transgenic rescue. Connect Tissue Res 44 Suppl 1, 264-271.

Odgren, P.R., Kim, N., Van Wesenbeeck, L., MacKay, C.A., Mason-Savas, A., Safadi, F.F., Popoff, S.N., Lengner, C., Van Hul, W., Choi, Y., et al. (2001). Evidence that the rat osteopetrotic mutation toothless (tl) is not in the TNFSF11 (TRANCE, RANKL, ODF, OPGL) gene. Int J Devel Biol 45, 853-859.

Odgren, P.R., MacKay, C.A., Mason-Savas, A., Yang, M., Mailhot, G., and Birnbaum, M.J. (2006b). False-positive beta-galactosidase staining in osteoclasts by endogenous enzyme: studies in neonatal and month-old wild-type mice. Connect Tissue Res 47, 229-234.

Odgren, P.R., and Marks, S.C., Jr. (1998). The complexities of osteoclast biology: lessons from eleven osteopetrotic mutations. Ital J Miner Electrolyte Metab 12, 9-13.

Odgren, P.R., Philbrick, W.M., and Gartland, A. (2003c). Perspective. Osteoclastogenesis and growth plate chondrocyte differentiation: emergence of convergence. Crit Rev Eukaryot Gene Expr 13, 181-193.

Odgren, P.R., Popoff, S.N., Safadi, F.F., MacKay, C.A., Mason-Savas, A., Seifert, M.F., and Marks, S.C., Jr. (1999). The toothless osteopetrotic rat has a normal vitamin D-binding protein-macrophage activating factor (DBP-MAF) cascade and chondrodysplasia resistant to treatments with colony stimulating factor-1 (CSF-1) and/or DBP-MAF. Bone 25, 175-181.

Odgren, P.R., Pratt, C.H., Mackay, C.A., Mason-Savas, A., Curtain, M., Shopland, L., Ichicki, T., Sundberg, J.P., and Donahue, L.R. (2010). Disheveled hair and ear (Dhe), a spontaneous mouse Lmna mutation modeling human laminopathies. PLoS One 5, e9959.

Perdu, B., Odgren, P.R., Van Wesenbeeck, L., Jennes, K., Mackay, C.C., and Van Hul, W. (2009). Refined Genomic Localization of the Genetic Lesion in the Osteopetrosis (op) Rat and Exclusion of Three Positional and Functional Candidate Genes, Clcn7, Atp6v0c, and Slc9a3r2. Calcif Tissue Int.

Safadi, F.F., Xu, J., Smock, S.L., Kanaan, R.A., Selim, A.H., Odgren, P.R., Marks, S.C., Jr., Owen, T.A., and Popoff, S.N. (2003). Expression of connective tissue growth factor in bone: its role in osteoblast proliferation and differentiation in vitro and bone formation in vivo. J Cell Physiol 196, 51-62.

Van Wesenbeeck, L., Odgren, P.R., Coxon, F.P., Frattini, A., Moens, P., Perdu, B., MacKay, C.A., Van Hul, E., Timmermans, J.P., Vanhoenacker, F., et al. (2007). Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 117, 919-930.

Van Wesenbeeck, L., Odgren, P.R., MacKay, C.A., D'Angelo, M., Safadi, F.F., Popoff, S.N., Van Hul, W., and Marks, S.C., Jr. (2002). The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification. Proc Natl Acad Sci U S A 99, 14303-14308.

van Wesenbeeck, L., Odgren, P.R., Mackay, C.A., and Van Hul, W. (2004). Localization of the gene causing the osteopetrotic phenotype in the incisors absent (ia) rat on chromosome 10q32.1. J Bone Miner Res 19, 183-189.

Xu, J., Smock, S.L., Safadi, F.F., Rosenzweig, A.B., Odgren, P.R., Marks, S.C., Jr., Owen, T.A., and Popoff, S.N. (2000). Cloning the full-length cDNA for rat connective tissue growth factor: implications for skeletal development. J Cell Biochem 77, 103-115.

Xu, Y., Morse, L.R., da Silva, R.A., Odgren, P.R., Sasaki, H., Stashenko, P., and Battaglino, R.A. (2010). PAMM: a redox regulatory protein that modulates osteoclast differentiation. Antioxid Redox Signal 13, 27-37.

Yang, M., Birnbaum, M.J., MacKay, C.A., Mason-Savas, A., Thompson, B., and Odgren, P.R. (2008). Osteoclast stimulatory transmembrane protein (OC-STAMP), a novel protein induced by RANKL that promotes osteoclast differentiation. J Cell Physiol 215, 497-505.

Yang, M., Mailhot, G., Birnbaum, M.J., MacKay, C.A., Mason-Savas, A., and Odgren, P.R. (2006a). Expression of and role for ovarian cancer G-protein-coupled receptor 1 (OGR1) during osteoclastogenesis. J Biol Chem 281, 23598-23605.

Yang, M., Mailhot, G., MacKay, C.A., Mason-Savas, A., Aubin, J., and Odgren, P.R. (2006b). Chemokine and chemokine receptor expression during colony stimulating factor-1-induced osteoclast differentiation in the toothless osteopetrotic rat: a key role for CCL9 (MIP-1g) in osteoclastogenesis in vivo and in vitro. Blood 107, 2262-2270.

Yang, M., and Odgren, P.R. (2005). Molecular cloning and characterization of rat CCL9 (MIP-1gamma), the ortholog of mouse CCL9. Cytokine 31, 94-102.