Spatiotemporal distribution of thrombospondin-4 and -5 in cartilage during endochondral bone formation and repair

Sastre, E. Andrés; Maly, Kathrin; Zhu, Mengjie; Witte-Bouma, Janneke; Trompet, Dana; Böhm, Anna-Marei; Brachvogel, Bent; Nieuwenhoven, Christianne A. van; Maes, Christa; Osch, Gerjo J.V.M. van; Zaucke, Frank; Farrell, Eric

doi:10.1016/j.bone.2021.115999

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…Interestingly, stimulation of keratinocytes with THBS4 yielded upregulation of their proliferation that well correlated with the hyperproliferative state of keratinocytes in psoriatic lesions that dwell in the vicinity of ECM containing abnormally high levels of THBS4. Nevertheless, THBS4 has been shown to specifically activate the migration of various cell types before, including other mesoderm-derived cells such as smooth muscle cells of different origin (Frolova et al, 2010;Girard et al, 2014;Lv X. et al, 2016;Su et al, 2017;Andres Sastre et al, 2021;Chou et al, 2021). Interestingly, our results on skin cell-type-selective responses to THBS4 stimulation are supported by previous studies on other tissues and cell types.…”

Section: Discussionsupporting

confidence: 89%

“…Interestingly, our results on skin cell-type-selective responses to THBS4 stimulation are supported by previous studies on other tissues and cell types. For example, Andres Sastre and colleagues reported recently that THBS4 stimulated endothelial cell but not bone marrow stromal cell migration (Andres Sastre et al, 2021). Studies with THBS4 −/− mice have shown that THBS4 does not affect neuronal cell proliferation but in contrast, promotes their migration (Girard et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

Klaas

Mäemets-Allas

Heinmäe

et al. 2021

Front. Cell Dev. Biol.

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Thrombospondin-4 (THBS4) is a non-structural extracellular matrix molecule associated with tissue regeneration and a variety of pathological processes characterized by increased cell proliferation and migration. However, the mechanisms of how THBS4 regulates cell behavior as well as the pathways contributing to its effects have remained largely unexplored. In the present study we investigated the role of THBS4 in skin regeneration both in vitro and in vivo. We found that THBS4 expression was upregulated in the dermal compartment of healing skin wounds in humans as well as in mice. Application of recombinant THBS4 protein promoted cutaneous wound healing in mice and selectively stimulated migration of primary fibroblasts as well as proliferation of keratinocytes in vitro. By using a combined proteotranscriptomic pathway analysis approach we discovered that β-catenin acted as a hub for THBS4-dependent cell signaling and likely plays a key role in promoting its downstream effects. Our results suggest that THBS4 is an important contributor to wound healing and its incorporation into novel wound healing therapies may be a promising strategy for treatment of cutaneous wounds.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

Klaas

Mäemets-Allas

Heinmäe

et al. 2021

Front. Cell Dev. Biol.

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“…Expression of THBS4 in knee cartilage was found to be correlated with OA disease severity [ 30 ]. A recent report showed that the expression of THBS4 is restricted to hypertrophic chondrocytes during endochondral bone formation, while COMP was distributed through all layers of cartilage [ 31 ]. Chondrocyte hypertrophy is suggested to play a role in the initiation and progression of OA [ 32 ], and our results (model 1, adjusted for age, sex and cell counts) open the possibility that THBS4 is a specific biomarker for chondrocyte hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression

Szilágyi¹,

Vallerga²,

Boer³

et al. 2022

Rheumatology

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Objectives The aim of this study was to identify biomarkers for radiographic osteoarthritis severity and progression acting within the inflammation and metabolic pathways. Methods For 3,517 Rotterdam Study participants, 184 plasma protein levels were measured using Olink inflammation and cardiometabolic panels. We studied associations with severity and progression of knee, hip, hand osteoarthritis, and a composite overall OA burden-score by multivariable regression models, adjusting for age, sex, cell counts and BMI. Results We found 18 significantly associated proteins for overall osteoarthritis burden, of which 5 stayed significant after multiple testing correction: circulating Cartilage acidic protein 1 (CRTAC1), Cartilage oligomeric matrix protein (COMP), Thrombospondin 4 (THBS4), Interleukin 18 receptor 1 (IL18R1) and Tumor necrosis factor ligand superfamily member 14 (TNFSF14). These proteins were also associated with progression of knee OA, with the exception of IL18R1. The strongest association was found for the level of CRTAC1 with 1 SD increase in protein level resulting in an increase of 0.09 (95%CI : 0.06–0.12) in overall osteoarthritis KLsum-score (p= 2.9x10−8), in the model adjusted for age, sex, BMI and cell counts. This association was also present with severity of osteoarthritis in all three joints, progression of knee osteoarthritis and was independent of BMI. We observed a stronger association for CRTAC1 with osteoarthritis than for the well-known osteoarthritis-biomarker COMP. Conclusion We identified several compelling biomarkers reflecting overall osteoarthritis burden and increased risk for osteoarthritis progression. CRTAC1 was the most compelling and robust biomarker for osteoarthritis severity and progression. Such a biomarker may be used for disease monitoring.

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“…THBS5 Interacts with several ECM components suggesting that THBS5 may play an important role in establishing and maintaining ECM structure by forming a molecular bridge between different components of the matrix or between the matrix and the cell membrane ( Budde et al, 2005 ). The expression of this protein has been found in chondrocytes, tendons, ligaments, smooth muscle cells, synovium, and osteoblasts ( Riessen et al, 2001 ; Andrés Sastre et al, 2021 ).…”

Section: Functions Of Matricellular Proteins In Cutaneous Wound Healingmentioning

confidence: 99%

Matricellular proteins in cutaneous wound healing

Cárdenas-León

Mäemets-Allas

Klaas

et al. 2022

Front. Cell Dev. Biol.

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Cutaneous wound healing is a complex process that encompasses alterations in all aspects of the skin including the extracellular matrix (ECM). ECM consist of large structural proteins such as collagens and elastin as well as smaller proteins with mainly regulative properties called matricellular proteins. Matricellular proteins bind to structural proteins and their functions include but are not limited to interaction with cell surface receptors, cytokines, or protease and evoking a cellular response. The signaling initiated by matricellular proteins modulates differentiation and proliferation of cells having an impact on the tissue regeneration. In this review we give an overview of the matricellular proteins that have been found to be involved in cutaneous wound healing and summarize the information known to date about their functions in this process.

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Spatiotemporal distribution of thrombospondin-4 and -5 in cartilage during endochondral bone formation and repair

Cited by 11 publications

References 48 publications

Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

Plasma proteomics identifies CRTAC1 as a biomarker for osteoarthritis severity and progression

Matricellular proteins in cutaneous wound healing

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