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Research

Deeper knowledge of basic skeletal cell biology has long-range implications for understanding many pervasive clinical conditions, such as osteoporosis, arthritis, and genetic conditions that affect bone growth. Our lab group studies how the cells of the skeleton function and how they communicate and regulate one another, with particular emphasis on the bone-resorbing osteoclast. Osteoclasts are large, multi-nucleated cells that begin life as mononuclear hematopoietic cells of the monocytes/macrophage lineage. Under the influence of specific growth factors (primarily CSF-1 and RANKL, or TRANCE), the precursors must migrate to the site of bone resorption, fuse, attach tightly to the bone, secrete protons and proteases which digest the bone matrix, then endocytose the dissolved material and transport it across the cell to be secreted.

Our main approach has been to start with rat and mouse models with genetic abnormalities that block osteoclast differentiation and/or activity, resulting in a condition called osteopetrosis. Osteopetrosis leads to dense, brittle bones lacking marrow spaces, failure of teeth to erupt through the jaws, and growth defects due to the inability to remove growth cartilage and to remodel growing bones. Through gene mapping and expression studies, we have identified novel effector genes which play critical roles in osteoclast biology. We have also applied advanced histopatholgical techniques to investigate the detailed impacts of gene function in the tissues, including upon angiogenesis and gene expression. We recently mapped the toothless and incisors absent (ia) mutations in the rat and in so doing discovered a novel gene which also causes osteopetrosis when mutated in humans. Efforts to map the last remaining naturally-occurring osteopetrotic mutation in a different rat strain are ongoing in the lab.

Our investigations of osteoclast biology are motivated by the need to learn more about how skeletal metabolism is regulated. We utilize a multifaceted approach, including genetics, transgenics, molecular biology, biochemistry, microscopy, gene expression, and protein function studies.

We have also investigated mechanisms of bone growth, especially the regulation of chondrocytes of the growth plate of endochondral bones – bones which form and grow via a cartilage model.

Some of our research findings over the past years are listed below:

  • 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., 1999)
  • 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., 2003)
  • Reported an improved method for generating high-activity non-radioactive probes for in situ hybridization in tissues (Odgren et al., 2003)
  • 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., 2006)
  • 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., 2006)
  • 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, we 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., 1999; Odgren et al., 2004; Odgren et al., 1997; Odgren and Marks, 1998; Odgren et al., 2003)