0976: LMPTP Drives Fibrosis in Systemic Sclerosis via TGF-beta Signaling Activation

Background/Purpose: The identification of effective and safe anti-fibrotic agents is a critical unmet need in systemic sclerosis (SSc). Although fibrosis in SSc is driven by aberrant activation of pro-fibrotic signaling pathways downstream of protein kinase receptors, such as the receptor for transforming growth factor beta (TGFbeta), little is known in this condition about phosphatases, which oppose signaling by kinases. We sought to explore a potential role for the low molecular weight PTP (LMPTP) in fibrotic manifestations of SSc because the LMPTP promotes growth signaling pathways in cancer cells, is highly expressed in fibroblasts and complete knockout (KO) of the LMPTP does not induce any spontaneous phenotype.

Methods: Skin biopsies and lung explants from patients with early SSc were subjected to in situ hybridization for LMPTP. Primary dermal fibroblasts (DF) were subjected to treatment with two independent LMPTP inhibitors followed by assessment of TGFbeta signaling, immunoprecipitations, transcriptomics, proteomics and phospho-proteomics analysis. TGFbeta signaling reporter assays were performed in 293 cells. Mice were subjected to the bleomycin model of skin and lung fibrosis.

Results: We found that the LMPTP is upregulated in fibrotic skin of scleroderma patients (Fig. 1). An assessment of primary DF treated with small-molecule LMPTP inhibitors showed that LMPTP promotes TGFbeta signaling (Fig. 2). Mechanistically, LMPTP promotes early TGFbeta receptor (TGFBR) signaling through the dephosphorylation of a novel substrate. Global deletion of LMPTP in mice significantly attenuated the severity of skin and lung fibrosis in the bleomycin-induced model (Fig. 3). Similar results were obtained when mice were treated with an orally bioavailable LMPTP inhibitor.

Conclusion: Taken together, these findings indicate a critical role for LMPTP in development of fibrosis through a novel mechanism of regulation of early TGFbeta signaling. As LMPTP KO mice are healthy and viable and LMPTP might be tractable for small molecule discovery, our study suggests that LMPTP inhibition is a potentially safe therapeutic strategy for preventing or treating fibrosis in scleroderma.