Role of PAPP-A in Graves' Ophthalmopathy

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PROJECT SUMMARY Graves’ Ophthalmopathy (GO) is the most serious extra-thyroidal complication that develops in patients with autoimmune Graves’ hyperthyroidism. It is characterized by increased orbital fat volume and extra-ocular muscle within the unyielding bony orbit, which can have deleterious consequences on eye function. Orbital decompression surgery is an effective but invasive treatment used for severe GO. A better understanding of the pathological mechanisms underlying GO may identify novel targets to inhibit the development and progression of GO before any clinical manifestation. Insulin-like growth factor-I receptor (IGF-IR) signaling has been found to be essential in promoting GO pathogenesis. A monoclonal antibody that binds to and blocks IGF-IR signaling, was recently FDA-approved for treatment of GO. However, adverse events have been documented, all likely due to the ubiquitous nature of IGF-IR. A better understanding of IGF signaling and its regulation in orbital tissue is needed to fully understand mechanism and avoid/reduce off-target consequences. One approach would be to target modifiers of IGF-IR signaling, instead of the IGF-IR per se. We propose PAPP-A as such a target. PAPP-A is a novel zinc metalloprotease that can increase pericellular IGF bioavailability through cleavage of inhibitory IGF binding proteins, in particular IGFBP-4. Conversely, inhibition of PAPP-A expression or its proteolytic activity represents an innovative approach to decrease IGF availability with resultant attenuation of IGF-IR signaling. Interestingly, the most potent stimulators of PAPP-A expression are pro-inflammatory cytokines, which are increased in orbital tissue from GO patients. We hypothesize that PAPP-A is a key modulator of IGF-R signaling in GO. Our Specific Aims are to: 1) Determine PAPP-A expression (basal and pro-inflammatory cytokine-induced) in orbital fibroblasts from GO patients and control subjects. 2) Determine the effect of a neutralizing monoclonal antibody that specifically inhibits PAPP-A- mediated IGFBP-4 proteolysis on IGF-I stimulated proliferation and differentiation in orbital fibroblasts from GO patients. We have primary fibroblasts from retro-orbital fat of GO patients at early passage in-hand and the experience with culture and analyses to establish feasibility. Preliminary results support a role for PAPP-A in GO. We anticipate outcomes from the proposed experiments that could ultimately lead to a novel targeted therapy for patients with GO.