STING mediates experimental osteoarthritis and mechanical allodynia in mouse.

BACKGROUND: This study was performed to develop therapeutic targets of osteoarthritis (OA) that can be targeted to alleviate OA development (i.e., cartilage destruction) and relieve the OA-associated joint pain. METHODS: The candidate molecule, STING (stimulator of interferon genes, encoded by Sting1), was identified by microarray analysis of OA-like mouse chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). STING functions in OA and hindpaw mechanical allodynia were evaluated by gain-of-function (intra-articular injection of a STING agonist) and loss-of-function (Sting1-/- mice) approaches. RESULTS: DNA damage was observed in OA-like chondrocytes. Cytosolic DNA sensors, STING and its upstream molecule, cGAS (cyclic GMP-AMP synthase), were upregulated in OA chondrocytes and cartilage of mouse and human. Genetic ablation of STING in mice (Sting1-/-) alleviated OA manifestations (cartilage destruction and subchondral bone sclerosis) and hindpaw mechanical allodynia. In contrast, stimulation of STING signaling in joint tissues by intra-articular injection of cGAMP exacerbated OA manifestations and mechanical sensitization. Mechanistic studies on the regulation of hindpaw mechanical allodynia revealed that STING regulates the expression of peripheral sensitization molecules in the synovium and meniscus of mouse knee joints. CONCLUSION: Our results indicated that STING, which senses damaged cytosolic DNA and accordingly activates the innate immune response, regulates OA pathogenesis and hindpaw mechanical allodynia. Therefore, inhibition of STING could be a therapeutic approach to inhibit OA cartilage destruction and relieve the associated mechanical sensitization in model mice.

Angiosarcoma after breast conservation: diagnostic pitfalls.

Angiosarcomas are aggressive tumors of endovascular origin. Although angiosarcomas are relatively rare, they are being reported with increasing frequency in patients who have previously undergone breast conserving therapy. The initial clinical presentation of angiosarcomas after breast irradiation is often similar to the presentation of recurrent breast carcinomas. In addition, the histologic and cytologic appearance of posttreatment angiosarcomas can be highly suggestive of recurrent breast carcinoma. Immunohistochemical stains are often required to make an accurate distinction between the 2 entities. An accurate diagnosis is essential, because prognosis and treatment are different for each condition. An early and accurate diagnosis is aided by a high index of suspicion by clinician and pathologist. Herein, a case history is presented that underscores the pitfalls in attempting to achieve an accurate diagnosis.