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Use of Multiphoton Imaging To Test Whether the Mechanism of Aberrant Endochondral Ossification (EO) in Hypomorphic Perlecan C1532Yneo Mice Leading To Avascular Necrosis (AVN) Is Due To Delayed Or Disrupted Vascularization
Olena Jacenko, Associate Professor of Animal Biology, Univ of Pennsylvania School of Veterinary Medicine.
Funding: NIH/NIDDK DK057904-09 Mechanisms of skeleto-hematopoietic differentiation (4/04 – 3/10).

Avascular necrosis (AVN), also called osteonecrosis, ischemic necrosis, or aseptic necrosis, is a debilitating skeletal condition affecting the general public.  AVN results from the loss of blood supply to the bone(s) of a joint and is most prevalent in the hips, shoulders, and knees of people in the prime of their careers, making this a particularly costly disorder affecting 10,000-to-20,000 new patients per year in the U.S. alone.  There is currently no non-surgical treatment for AVN, and natural animal models are lacking to facilitate treatment development.  Our hypomorphic perlecan C1532Yneo mice (Rodgers et al, 2007), which lack wildtype (WT) levels of perlecan, a large (~450 kDa) extracellular proteoglycan (Iozzo et al, 1994), present with early and acute AVN-like disease.  The objective of this project is to examine the vascular invasion and delivery of small molecules to the growth plate of our genetically engineered perlecan deficient mice compared to wildtype controls using multiphoton imaging.

We hypothesize that vascular delivery to the growth plates of these animals is impaired due to the altered basement membranes of supplying blood vessels and/or due to the observed alterations in EO.  Because perlecan has been shown to sequester cytokines, establish molecular gradients, and mediate growth factor signaling, we additionally hypothesize that C1532Yneo growth plates lacking adequate levels of perlecan are more leaky than WT growth plates, and are thus less capable of retaining and properly distributing small molecules entering the growth plate via vascular delivery.  Therefore, future studies would potentially include the use of fluorescently labeled biological agents such as vascular endothelial growth factor and basic fibroblast growth factor.  These molecules have been shown to interact with perlecan and may be delivered to the growth plate through the vascular system.  Such studies would provide a direct mechanistic link between altered vascular delivery and impaired EO.  Initial studies are using DRBIO facilities and protocols that have been developed through the Farnum collaboration.


Rodgers, K.D., Sasaki, T., Aszodi, A. & Jacenko, O. Reduced perlecan in mice results in chondrodysplasia resembling Schwartz-Jampel syndrome. Hum Mol Genet 16, 515-28 (2007).

Iozzo, R.V., Cohen, I.R., Grassel, S. & Murdoch, A.D. The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J 302 (Pt 3), 625-39 (1994).






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