Cartilage and Bone Development:
The driving question of my current research is: How is chondrocyte and osteoblast maturation regulated? I have conducted studies focusing on TGFβs role in chondrocyte differentiation as well as the role of extracellular matrix and metalloproteases (MMPs) in promotion of chondrocyte maturation, mineralization and osteoblast differentiation. Questions concerning chondrocyte hypertrophy are addressed at the transcriptional, translational and post-translational levels; specifically, the role of TGFβ at later stages of chondrocyte hypertrophy and early stages of osteoblast differentiation and the role of MMP-13 in mineralization of the growth plate and activation of hypertrophic chondrocyte-produced TGFβ2.
Web-based Gross Anatomy Prosection Videos:
We have designed a learning aid that includes both a series of video clips that provide the students visual guidance about how to dissect and a companion laboratory dissection manual. The videos are not intended to be an anatomy atlas, but more to facilitate student dissections while they are working independently. The videos are accessible via Blackboard, the web-based teaching aid on campus. We will obtain feedback from students in our DO, MS and PhD programs about the effectiveness of the video clips demonstrating various prosections to facilitate learning in the laboratory portion of the human gross anatomy course.
Animal Models for the Study of Mucopolysaccharidoses and Joint Disease:
This project investigates the pathophysiology of cartilage and bone disease in mucopolysaccharidosis type VI, (MPS VI), an inherited lysosomal storage disorder due to deficient N-acetylgalactosamine-4-sulfatase (NAG4S) activity. The underlying hypothesis of our research is that glycosaminoglycan (GAG) accumulation in MPS connective tissue cells causes enhanced apoptosis and/or proliferation, and that this, in turn, results in abnormal matrix homeostasis leading to the characteristic bone and joint abnormalities. We also hypothesize that inflammation plays an important role in the pathogenesis of bone and joint disease in MPS VI (and perhaps other MPS diseases), and that anti-inflammatory therapeutic strategies might be beneficial for these patients. Finally, we hypothesize that the efficacy of metalloprotease replacement therapy in MPS bones and joints can be improved by modifying the recombinant enzymes such that they more efficiently penetrate connective tissue matrices.
East Coast Connective Tissue Society Young Investigator Award 1999: "MMP-13 expression during chondrocyte maturation."
Orthopaedic Research Society New Investigator Recognition Award 1997: "Changes in TGFβ activation and isoform profiles accompany endochondral ossification."
Orthopaedic Research Society New Investigator Recognition Award Semi-Finalist 1996: "Endogenously produced articular chondrocyte factors inhibit growth plate chondrocyte maturation."
As Principle Investigator:
- CCDA Pilot Grant 10/07-10/08 "Hypertrophic chondrocytes produce a large latent TGFβ complex that includes MMP13"
- NIAMS RO3 7/96 to 6/98 "TGFβs and Craniofacial Skeletal Development"
- NIH RO3 DE11876
- NICDR National Research Service Award 8/95 to 7/97 "Control of Craniofacial Skeletal Development by TGFβs"
- NIH F32 DE05675
- NIDDK 5/05 to 4/09 "MPS VI and I feline model" - collaborator
- NIDDK 2/02 to 1/07 "MPS VII canine model" - collaborator
- National MPS Society Grant 7/05 to 6/07 "Biomarkers and treatments for joint pathology in MPS VI" - collaborator
- National MPS Society Grant 7/03 to 6/05 "Joint pathology in MPS VI" - collaborator
Simonaro, C.M.; M. D'Angelo; X. He; E. Eliyahu; N. Shtraizent; M.E. Haskins and E.H. Schuchman (2007) "Mechanism of glycosaminoglycan-mediated disease: Implications for the Mucopolysaccharidoses and other connective tissue diseases." Journal of Pathology Accepted 09/07
DiLullo, C; Coughlin, P; D'Angelo, M; McGuinness, M; Bandle, J; Slotkin, EM; Shainker, SA; Wenger, C and SJ Berray (2006) "Anatomy in a New Curriculum: Facilitating the Learning of Gross Anatomy using web access streaming dissection videos." Journal of Visual Communication in Medicine 29(3): 99-108
Simonaro, C.M; D'Angelo, M.; Haskins, ME and EH Schuchman (2005) "Joint and bone disease in the mucopolysaccharidoses: Identification of new therapeutic targets and biomarkers, and analogies to arthritis." Pediatric Research 57(5):701-707
Volk, S.W.; Kapatkin, A.S.; Haskins, M.E.; Walton, R.M.; D'Angelo, M. (2003) "Gelatinase activity in synovial fluid and synovium from osteoarthritic canine joints." American Journal of Veterinary Research 64:1193-1328.
Chen, E.; Yuan, Z-A.; Wright, J.T.; Hong, S.P.; Li, Y.; Collier, P.M.; Hall, B.; D'Angelo, M.; Decker, S.; Piddington, R.; Abrams, W.R.; Kulkarni, A.B.; Gibson, C.W. (2003) "The small bovine amelogenin LRAP fails to rescue the amelogenin null phenotype." Calcified Tissue International Online First, September 10, 2003
Wesenbeck, L.V.; Odgren P.R.; D'Angelo, M.; Safadi, F.F.; Popoff, S.N.; VanHul, W.; Marks, S.C. (2002) "The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat CSF1 gene: new evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification." Proceedings of the National Academy of Science USA 99: 14303-308.
D'Angelo, M; Sarment, DP; Billings, PC; Pacifici, M. (2001) Activation of TGF-beta in chondrocytes undergoing endochondral ossification. Journal of Bone and Mineral Research 16: 2339-2347.
D'Angelo, M; Billings, PC; Pacifici, M; Leboy, PS; Kirsch, T (2001) Authentic matrix vesicles contain active metalloproteases: A role for matrix vesicle-associated MMP-13 in activation of TGF-β Journal of Biological Chemistry 276:11347-53.
Volk, S.W.; D'Angelo, M.; Diefenderfer, D. and P.S. Leboy. (2000). "Utilization of bone morphogenetic protein receptors during chondrocyte maturation." Journal of Bone and Mineral Research 15:1630-1639.
D'Angelo, M.; Yan, Z.; Nooreyazdan, M.; Pacifici, M.; Sarment, D.S.; Billings, P. C. and P.S. Leboy (2000). "MMP-13 is induced during chondrocyte hypertophy." Journal of Cellular Biochemistry 77:678-693.