Abstract
Heterotopic ossification (HO) is defined as abnormal differentiation of local stromal cells of mesenchymal origin, resulting in pathologic cartilage and bone matrix deposition. Cyr61, CTGF, Nov (CCN) family members are matricellular proteins that have diverse regulatory functions on cell proliferation and differentiation, including the regulation of chondrogenesis. However, little is known regarding CCN family member expression or function in HO. Here, a combination of bulk and single-cell RNA sequencing defined the dynamic temporospatial pattern of CCN family member induction within a mouse model of trauma-induced HO. Among CCN family proteins, Wisp1 (also known as Ccn4) was most upregulated during the evolution of HO, and Wisp1 expression corresponded with chondrogenic gene profile. Immunohistochemistry confirmed WISP1 expression across traumatic and genetic HO mouse models as well as in human HO samples. Transgenic Wisp1LacZ/LacZ knockin animals showed an increase in endochondral ossification in HO after trauma. Finally, the transcriptome of Wisp1-null tenocytes revealed enrichment in signaling pathways, such as the STAT3 and PCP signaling pathways, that may explain increased HO in the context of Wisp1 deficiency. In sum, CCN family members, and in particular Wisp1, are spatiotemporally associated with and negatively regulate trauma-induced HO formation.
Highlights
Heterotopic ossification (HO) is the abnormal collection of bone and cartilage matrix in soft tissues, incited by traumatic insult [1]
Several potential downstream signaling pathways altered among Wisp1–/–adipose stromal cells were identified that would predispose to a chondrogenic phenotype, including STAT3 [32], PKA [31], and p38 MAPK signaling [34]
Data in osteoarthritis have shown a decrease in cartilage degeneration and an increase in cartilage matrix formation in Wisp1-knockout mice, and similar findings in WISP1 stimulated osteoarthritic human chondrocytes [19, 20]
Summary
Heterotopic ossification (HO) is the abnormal collection of bone and cartilage matrix in soft tissues, incited by traumatic insult [1]. Predominantly local stromal/fibroblastic cells of mesenchymal origin within connective tissue [3, 4, 6,7,8] undergo abnormal osteochondral differentiation producing pathologic extracellular matrix of bone and cartilage [1, 9]. WISP1 appears to play an aggravating role in cartilage degradation in osteoarthritis, potentially through an increase in expression of matrix metalloproteinases [19, 20]. Despite their roles in modulating osteochondral cell proliferation and differentiation, virtually nothing is known regarding CCN family members, including WISP1, in the aberrant cell fate determination seen in HO
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