Synovial joints such as those that comprise the elbow, knee, and hip are extremely important for functioning in everyday life. Congenital defects, disease, and trauma to synovial joints, in particular to the articular cartilage that comprises a joint, are debilitating to billions of people. Short of total joint replacement, therapies to bring the joint back to its normal functioning condition are sorely lacking. Impeding the progress of clinical measures is the inherent inability of articular cartilage to repair or regenerate itself. Thus, before joint repair procedures based on regeneration, i.e., regenerative medicine, are to be tested and utilized, there must be an understanding of the regeneration process of the tissues that comprise a joint. Until now, however, there has not been a study focused on regeneration of a synovial joint. The investigator proposes a model of joint regeneration and a novel means with which to study the regeneration process. Using the embryonic chick model, her preliminary data show that the presumptive elbow joint is able to regenerate following removal, and this ability is subsequently lost with increasing developmental age as evidenced by the lack of an elbow joint and what appear as cartilage fusions between elements. The proposed model of joint regeneration asserts that cells of the prospective skeletal elements that comprise the elbow, the humerus, radius, and ulna are first observed as continuous mesenchymal condensations. Genes associated with prechondrogenic or early condensations are observed. Subsequently, these genes are down regulated in the region of joint formation and genes regulating joint morphogenesis are expressed in the regenerating joint. The investigator'model purports that lack of joint morphogenetic signals during the healing process, results in limbs in which the skeletal elements are formed without an intervening elbow joint. In addition to this model of joint regeneration, she hypothesizes that the chick elbow is able to initiate regeneration following removal because of the presence and/or activation of a member(s) of the fibroblast growth factor (FGF) family. Based on studies of regenerating limbs/fins in urodeles (salamanders and newts), anurans (frogs), and zebrafish, there is strong evidence that Fgf signaling is required for the early stages of regeneration. Using histology, cell labeling, microscopy, and gene expression, the investigator will verify the model of joint regeneration. Using growth factor delivery (gain of function), inhibitor analysis (loss of function), and RT-PCR, she will verify a role for FGFs in the initiation of regeneration. The long-term goal of this project is to elucidate the factors required to regenerate the tissues that make up a joint, including muscle, bone, and cartilage.
The specific aims are designed to test the model of joint regeneration and the hypothesis that Fgf(s) is required for the initiation of joint regeneration in the developing chick. This work will lay a foundation that will have significant implications in the fields of joint development and regenerative medicine.
At some point in most everyone's life, joint integrity will be diminished either through trauma, disease, aging, or congenital defects. The research outlined in this proposal offers a way to study, for the first time, how tissues of the limb are able to initiate regeneration of a joint. By studying this process, investigators will be that much closer to achieving regenerative repair in humans.
|Özpolat, B Duygu; Zapata, Mariana; Daniel Frugé, John et al. (2012) Regeneration of the elbow joint in the developing chick embryo recapitulates development. Dev Biol 372:229-38|