Wisp inhibits chondrogenic differentiation in heterotopic ossification

Heterotopic ossification (HO) is the formation of extra-skeletal bone in muscle and soft tissues. Better characterization of the signaling pathways predisposing to HO is critical to identifying therapies directed against this common and potentially debilitating condition. WISP-1 (WNT1-inducible-signaling pathway protein 1) is a CCN family member and is expressed in skeletal cells during bone development or repair. Here, we sought to comprehensively explore the significance of WISP-1 across mouse and human HO. Among CCN family members, local Wisp1 expression was most highly upregulated within experimental trauma-associated HO by RNA sequencing, and increased Wisp1 corresponded to gene markers of osteochondral differentiation. WISP1 immunolocalization demonstrated conserved expression in osteochondral cells across mouse and human HO, including an FOP-like model, post-traumatic model, and human examples of non-genetic HO. Transgenic Wisp1 global knockout demonstrated an increase in cartilage and bone in a trauma-induced HO model. Microarray and in vitro culture of Wisp1 null cells suggested that WISP1 functions as a negative regulator of chondrogenic differentiation, and that Wisp1 deletion results in unrestrained endochondral HO formation. siRNA mediated WISP1 knockdown in human progenitor cells confirmed this finding. Overall, these findings suggest that endogenous WISP1 has pathophysiologic relevance in trauma-induced HO and functions as a negative regulator of ectopic chondrogenesis. compare WT and Wisp1 KO mice adipose derived stromal cell from inguinal fat pad, 1 sample of each class