Endogenous CCN family member WISP1 inhibits trauma-induced heterotopic ossification

Hsu, Ginny Ching Yun; Marini, Simone; Negri, Stefano; Wang, Yiyun; Xu, Jiajia; Pagani, Chase A.; Hwang, Charles; Stepien, David M.; Meyers, Carolyn A.; Miller, Sarah; McCarthy, Edward F.; Lyons, Karen M.; Levi, Benjamin; James, Aaron W.

doi:10.1172/jci.insight.135432

Cited by 14 publications

(12 citation statements)

References 53 publications

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“…However, micro-CT imaging observed the ectopic bone in the present study at 6 weeks post-surgery. Although a previous study suggested that NIR imaging with IRDye 680RD BoneTag could detect heterotopic mineralization 5 days after surgery in the same HO model, 14 only cartilage is produced within 3 weeks after surgery, 19,20,35 which was consistent with the results of Safranin O-Fast Green staining in our experiment. We speculated that this might be because the probe was also involved in other biological processes during the formation of HO.…”

Section: Discussionsupporting

confidence: 91%

“…However, few modalities with high sensitivity and specificity are currently available concerning the early diagnosis of HO in the clinic. Since cartilage is the main component of the lesion in the early stage of HO, 19 we thus believe that targeting cartilage formation offers a potential approach for the early diagnosis of HO. In this study, we synthesized a NIR fluorescent probe WL-808 with an ideal cartilage affinity by conjugating NIR dye IR-808 with a cartilage-targeting peptide WYRGRL, which can efficiently penetrate cartilage extracellular matrix and specifically bind to Col2a1.…”

Section: Discussionmentioning

confidence: 99%

“…Predominantly local tissue-resident mesenchymal progenitor cells (MPCs) undergo abnormal osteochondral differentiation producing pathological extracellular matrix of the cartilage and bone. 19,20 Therefore, if HO can be diagnosed at the early phase of HO development-cartilage formation, the treatment can be initiated earlier, and subsequent progression will be prevented. Similar to normal articular cartilage, the cartilaginous lesion of HO is composed mainly of type II collagen (Col2a1), 21 which provides an opportunity for chondrocyte-targeted imaging.…”

Section: Introductionmentioning

confidence: 99%

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Early diagnosis of heterotopic ossification with a NIR fluorescent probe by targeting type II collagen

Wang

et al. 2023

J. Mater. Chem. B

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Early diagnosis of heterotopic ossification with a NIR fluorescent probe by targeting type II collagen

Wang

et al. 2023

J. Mater. Chem. B

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“…S1 ). 16 , 17 , 19 Recently, our group identified that this extremity injury results in an acute increase in NGF (Nerve growth factor) expression at early timepoints, which drives NGF-responsive nerve ingrowth into the incipient HO site. 8 A previously established single-cell RNA sequencing (scRNA-Seq) dataset was used to further interrogate neurotrophins and their receptors after HO inducing injury.…”

Section: Resultsmentioning

confidence: 99%

TrkA+ Neurons Induce Pathologic Regeneration After Soft Tissue Trauma

Cherief

Negri

Qin

et al. 2022

Stem Cells Translational Medicine

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Heterotopic ossification (HO) is a dynamic, complex pathologic process that often occurs after severe polytrauma trauma, resulting in an abnormal mesenchymal stem cell differentiation leading to ectopic bone growth in soft-tissues including tendons, ligaments, and muscles. The abnormal bone structure and location induce pain and loss of mobility. Recently, we observed that NGF (Nerve growth factor)-responsive TrkA (Tropomyosin receptor kinase A)-expressing nerves invade sites of soft-tissue trauma, and this is a necessary feature for heterotopic bone formation at sites of injury. Here, we assayed the effects of the partial TrkA agonist Gambogic amide (GA) in peritendinous heterotopic bone after extremity trauma. Mice underwent HO induction using the burn/tenotomy model with or without systemic treatment with GA, followed by an examination of the injury site via radiographic imaging, histology, and immunohistochemistry. Single-cell RNA Sequencing confirmed an increase in neurotrophin signaling activity after HO-inducing extremity trauma. Next, TrkA agonism led to injury site hyper-innervation, more brisk expression of cartilage antigens within the injured tendon, and a shift from FGF to TGFβ signaling activity among injury site cells. Nine weeks after injury, this culminated in higher overall levels of heterotopic bone among GA-treated animals. In summary, these studies further link injury site hyper-innervation with increased vascular ingrowth and ultimately heterotopic bone after trauma. In the future, modulation of TrkA signaling may represent a potent means to prevent the trauma-induced heterotopic bone formation and improve tissue regeneration.

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“…In bone biology, CCNs have been implicated in physiological development, turnover, and regeneration. For example, CCN1 modulates mature osteoblast and osteocyte function to affect bone mass 11 , CCN2 regulates and coordinates osteoblast differentiation in skeletal development 12 and CCN4 regulates osteogenesis by enhancing BMP2 (bone morphogenic protein-2) activity and is also important for bone turnover 13,14 . With respect to CCN3, in vivo studies support the notion that CCN3 negatively regulates bone regeneration via mechanisms involving BMP2 15 .…”

Section: Introductionmentioning

confidence: 99%

Myeloid CCN3 protects against aortic valve calcification

Zhou

et al. 2022

Preprint

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Background Cellular communication network factor 3 (CCN3) has been implicated in the regulation of osteoblast differentiation. However, it is not known if CCN3 can regulate valvular calcification. While macrophages have been shown to regulate valvular calcification, the molecular and cellular mechanisms of this process remain poorly understood. In the present study, we investigated the role of macrophage-derived CCN3 in the progression of calcific aortic valve disease. Methods Myeloid-specific knockout of CCN3 (Mye-CCN3-KO) and control mice were subjected to a single tail intravenous injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9) to induce hyperlipidemia. AAV-injected mice were then fed a high fat diet for 40 weeks. At the conclusion of high fat diet feeding, tissues were harvested and subjected to histologic and pathologic analyses. Echocardiography was performed prior to the termination of experiments to assess cardiac and valvular function. In vitro, bone marrow–derived macrophages (BMDMs) from both control and Mye-CCN3-KO were utilized to explore how myeloid CCN3 affects the calcification process. To assess the impact of macrophage CCN3 deficiency on valvular intersititial cells (VIC) calcification, human VICs were cultured with conditioned media from CCN3-deficient BMDMs, followed by Alazarin red staining and gene expression analysis. Results Echocardiography revealed that both male and female Mye-CCN3-KO mice displayed compromised aortic valvular function accompanied by exacerbated valve thickness and cardiac dysfunction. Histologically, Alizarin-Red staining revealed a marked increase in aortic valve calcification in Mye-CCN3-KO mice when compared to the controls. In vitro, CCN3 deficiency augmented BMP2 production and secretion from bone marrow-derived macrophages. In addition, human valvular interstitial cells cultured with conditioned media from CCN3-deficient BMDMs resulted in exaggerated pro-calcifying gene expression and the consequent calcification. Conclusion Our data uncovered a novel role of myeloid CCN3 in the regulation of aortic valve calcification. Modulation of BMP2 production and secretion in macrophages might serve as a key mechanism for macrophage-derived CCN3’s anti-calcification function in the development of CAVD.

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Endogenous CCN family member WISP1 inhibits trauma-induced heterotopic ossification

Cited by 14 publications

References 53 publications

Early diagnosis of heterotopic ossification with a NIR fluorescent probe by targeting type II collagen

Early diagnosis of heterotopic ossification with a NIR fluorescent probe by targeting type II collagen

TrkA+ Neurons Induce Pathologic Regeneration After Soft Tissue Trauma

Myeloid CCN3 protects against aortic valve calcification

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