Collagen remodeling is an integral part of tissue development, maintenance, and regeneration, but excessive remodeling is associated with various pathologic conditions. The ability to target collagens undergoing remodeling could lead to new diagnostics and therapeutics as well as applications in regenerative medicine; however, such collagens are often degraded and denatured, making them difficult to target with conventional approaches. Here, we present caged collagen mimetic peptides (CMPs) that can be phototriggered to fold into triple helix and bind to collagens denatured by heat or by matrix metalloproteinase (MMP) digestion. Peptidebinding assays indicate that the binding is primarily driven by stereo-selective triple-helical hybridization between monomeric CMPs of high triple-helical propensity and denatured collagen strands. Photo-triggered hybridization allows specific staining of collagen chains in protein gels as well as photo-patterning of collagen and gelatin substrates. In vivo experiments demonstrate that systemically delivered CMPs can bind to collagens in bones, as well as prominently in articular cartilages and tumors characterized by high MMP activity. We further show that CMP-based probes can detect abnormal bone growth activity in a mouse model of Marfan syndrome. This is an entirely new way to target the microenvironment of abnormal tissues and could lead to new opportunities for management of numerous pathologic conditions associated with collagen remodeling and high MMP activity.A s the most abundant protein in mammals, collagens play a crucial role in tissue development and regeneration, and their structural or metabolic abnormalities are associated with debilitating genetic diseases and various pathologic conditions. Although collagen remodeling occurs during development and normal tissue maintenance, particularly for renewing tissues (e.g., bones), excess remodeling activity is commonly seen in tumors, arthritis, and many other chronic wounds. During collagen remodeling, large portions of collagens are degraded and denatured by proteolytic enzymes, which can be explored for diagnostic and therapeutic purposes. Since unstructured proteins are not ideal targets for rational drug design, library approaches have been employed to develop monoclonal antibody (1, 2) and peptide probes (3) that specifically bind to cryptic sites in collagen strands that become exposed when denatured. However, these probes suffer from poor pharmacokinetics (4), and/or low specificity, and binding affinity (5).We envisioned that triple helix, the hallmark structural feature of collagen, could provide a unique targeting mechanism for the denatured collagens. The triple helix is nearly exclusively seen in collagens except as small subdomains in a few noncollagen proteins (6). Considering its striking structural similarity to the DNA double helix in terms of multiplex formation by periodic interchain hydrogen bonds along the polymer backbone (6), we thought that a small peptide sequence with strong triple-helix prope...
Skull base osteomyelitis in the setting of granulomatosis with polyangiitis (GPA) is rare and entails significant diagnostic challenges. We present a case of a 65-year-old Caucasian man with a history of rheumatoid arthritis, off immunosuppression for 18 months, who presented with 2 years of chronic headaches, severe fatigue, saddle nose deformity and 20-kilogram unintentional weight loss. Maxillofacial CT revealed an extensive destructive sinonasal and erosive skull base process. Laboratory evaluation showed equivocal elevation of antiproteinase 3 antibodies with negative antineutrophil cytoplasmic antibody panel. Biopsy of the skull base/clivus revealed necrotising granulomatous inflammation with focal vasculitis consistent with GPA, and multiple bone cultures were positive for Pseudomonas aeruginosa. This patient was diagnosed concurrently with GPA and P. aeruginosa skull base osteomyelitis. He was started on a 6-week course of cefepime intravenously and oral prednisone, with the plan to initiate rituximab infusion 2 weeks after initiation of antibiotic therapy.
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