BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a

Bertrand, Jessica; Kräft, T.; Gronau, T.; Sherwood, J.; Rutsch, Frank; Lioté, Frédéric; Dell'Accio, F.; Lohmann, Christoph H.; Bollmann, M.; Held, Annelena; Pap, Thomas

doi:10.1136/annrheumdis-2019-216648

Cited by 41 publications

(33 citation statements)

References 56 publications

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“…Calciumcontaining crystals, which encompass basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate crystals (CPPD), have been demonstrated to be of etiologic importance in OA. Indeed they were shown to actively trigger inflammatory, catabolic and oxidant responses in joint cells such as synovial fibroblasts, macrophages, osteoclasts and chondrocytes (Fuerst et al, 2009;Nasi et al, 2016b;Bertrand et al, 2020;Yan et al, 2020). However, the receptors and signaling pathways modulating ectopic calcification in OA joints only start to be elucidated (Castelblanco et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

Ehirchiou¹,

Bernabei²,

Chobaz³

et al. 2020

Front. Cell Dev. Biol.

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Osteoarthritis (OA) is a progressive joint disease that is strongly associated with calcium-containing crystal formation (mineralization) by chondrocytes leading ultimately to cartilage calcification. However, this calcification process is poorly understood and treatments targeting the underlying disease mechanisms are lacking. The CD11b/CD18 integrin (Mac-1 or αMβ2), a member of the beta 2 integrin family of adhesion receptors, is critically involved in the development of several inflammatory diseases, including rheumatoid arthritis and systemic lupus erythematosus. We found that in a collagen-induced arthritis, CD11b-deficient mice exhibited increased cartilage degradation compared to WT control animals. However, the functional significance of CD11b integrin signaling in the pathophysiology of chondrocytes remains unknown. CD11b expression was found in the extracellular matrix and in chondrocytes in both healthy and damaged human and murine articular cartilage. Primary murine CD11b KO chondrocytes showed increased mineralization when induced in vitro by secondary calciprotein particles (CPP) and quantified by Alizarin Red staining. This increased propensity to mineralize was associated with an increased alkaline phosphatase (Alp) expression (measured by qRT-PCR and activity assay) and an enhanced secretion of the pro-mineralizing IL-6 cytokine compared to control wild-type cells (measured by ELISA). Accordingly, addition of an anti-IL-6 receptor antibody to CD11b KO chondrocytes reduced significantly the calcification and identified IL-6 as a pro-mineralizing factor in these cells. In the same conditions, the ratio of qRT-PCR expression of collagen X over collagen II, and that of Runx2 over Sox9 (both ratio being indexes of chondrocyte hypertrophy) were increased in CD11b-deficient cells. Conversely, the CD11b activator LA1 reduced chondrocyte mineralization, Alp expression, IL-6 production and collagen X expression. In the meniscectomy (MNX) model of murine knee osteoarthritis, deficiency of CD11b led to more severe OA (OARSI scoring of medial cartilage damage in CD11b: 5.6 ± 1.8, in WT: 1.2 ± 0.5, p < 0.05, inflammation in CD11b: 2.8 ± 0.2, in WT: 1.4 ± 0.5). In conclusion, these data demonstrate that CD11b signaling prevents chondrocyte hypertrophy and chondrocyte mineralization in vitro and has a protective role in models of OA in vivo.

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Section: Introductionmentioning

confidence: 99%

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

Ehirchiou¹,

Bernabei²,

Chobaz³

et al. 2020

Front. Cell Dev. Biol.

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“…This mutation also delayed development of the left acetabulum and left glenoid fossa, as observed by Alcian blue staining in 8-week-old knock-in mutant mice [5]. Feldeman et al found that MMP13, which is related to chondrogenesis [18], was overexpressed in femur-derived bone cells of knock-in mice [5]. Previous studies showed that TENM3 is related to cartilage formation and expressed in prechondrogenic mesenchymal cells.…”

Section: Discussionmentioning

confidence: 89%

Replicative Verification of Susceptibility Genes Previously Identified from Families with Segregating Developmental Dysplasia of the Hip

Wang²,

Chen

et al. 2020

Preprint

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Background: Developmental dysplasia of the hip (DDH) is a complex hip joint deformity with effects ranging from acetabulum malformation to irreversible hip dislocation. Previous studies suggest a significant association of four variations, Teneurin transmembrane protein 3 (TENM3) (chr4:183721398), Heparan sulfate proteoglycan 2 (HSPG2) (chr1:22201470), ATPase plasma membrane Ca2+ transporting 4 (ATP2B4) (chr1:203682345), and Prostaglandin F receptor (PTGFR) (chr1:79002214), with DDH susceptibility in families with segregating DDH. However, the association was not validated in sporadic cases and remains controversial. To confirm the association of the reported variations in these four genes with DDH, we conducted replicative verification in 250 sporadic samples with DDH from a Chinese Han population. Methods: We conducted Sanger sequencing after amplifying the variation sites. The results were compared with the reference sequence from the GRCh37 assembly in UCSC (http://genome.ucsc.edu). Results: Replication analysis of 250 sporadic samples by Sanger sequencing indicated that the four variations, TENM3 (chr4:183721398), HSPG2 (chr1:22201470), ATP2B4 (chr1:203682345), and PTGFR (chr1:79002214), were not associated with the susceptibility to DDH in the Chinese Han population.Conclusions: Further studies should be performed to identify other variations of these four genes that are potentially associated with DDH by whole-exome sequencing and the results should be verified in different populations.

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“…However, CPPD crystals themselves did only induce a minor increase in p16 expression, but have no change in the amount of β-Gal-positive cells (Figure 3C). BCP crystals have been shown to induce hypertrophic differentiation of chondrocytes by activating the canonical Wnt signaling pathway (Bertrand et al, 2020). However, no effect of BCP crystals on chondrocyte senescence markers was detected (Figure 3C).…”

Section: Discussionmentioning

confidence: 94%

“…Sterile, pyrogen-free BCP crystals were synthesized as previously described (Bertrand et al, 2020). Triclinic CPPD crystals were purchased from InvivoGen.…”

Section: Basic Calcium Phosphate and Calcium Pyrophosphate Dihydrate Crystal Stimulationmentioning

confidence: 99%

“…Basic calcium phosphate crystal deposition has been attributed to hypertrophic differentiation of chondrocytes during OA (Fuerst et al, 2009a). Furthermore, BCP crystals have been implicated in various signaling pathways including the inflammatory signaling pathways and canonical WNT signaling (Ea et al, 2013;Nasi et al, 2016Nasi et al, , 2017Bertrand et al, 2020). Besides hypertrophic differentiation of chondrocytes, also apoptosis and senescence have been associated with the OA chondrocyte phenotype (McCulloch et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Chondrocytes From Osteoarthritic and Chondrocalcinosis Cartilage Represent Different Phenotypes

Meyer¹,

Dittmann²,

Kornak³

et al. 2021

Front. Cell Dev. Biol.

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Basic calcium phosphate (BCP)-based calcification of cartilage is a common finding during osteoarthritis (OA) and is directly linked to the severity of the disease and hypertrophic differentiation of chondrocytes. Chondrocalcinosis (CC) is associated with calcium pyrophosphate dihydrate (CPPD) deposition disease in the joint inducing OA-like symptoms. There is only little knowledge about the effect of CPPD crystals on chondrocytes and the signaling pathways involved in their generation. The aim of this study was to investigate the chondrocyte phenotype in CC cartilage and the effect of CPPD crystals on chondrocytes. Cartilage samples of patients with CC, patients with severe OA, and healthy donors were included in this study. The presence of CC was evaluated using standard X-ray pictures, as well as von Kossa staining of cartilage sections. OA severity was evaluated using the Chambers Score on cartilage sections, as well as the radiological Kellgren–Lawrence Score. Patients with radiologically detectable CC presented calcification mainly on the cartilage surface, whereas OA patients showed calcification mainly in the pericellular matrix of hypertrophic chondrocytes. OA cartilage exhibited increased levels of collagen X and matrix metalloproteinase 13 (MMP13) compared with CC and healthy cartilage. This observation was confirmed by qRT-PCR using cartilage samples. No relevant influence of CPPD crystals on hypertrophic marker genes was observed in vitro, whereas BCP crystals significantly induced hypertrophic differentiation of chondrocytes. Interestingly, we observed an increased expression of p16 and p21 in cartilage samples of CC patients compared with OA patients and healthy controls, indicating cellular senescence. To investigate whether CPPD crystals were sufficient to induce senescence, we incubated chondrocytes with BCP and CPPD crystals and quantified senescence using β-gal staining. No significant difference was observed for the staining, but an increase of p16 expression was observed after 10 days of culture. Primary chondrocytes from CC patients produced CPPD crystals in culture. This phenotype was stabilized by mitomycin C-induced senescence. Healthy and OA chondrocytes did not exhibit this phenotype. BCP and CPPD crystals seem to be associated with two different chondrocyte phenotypes. Whereas BCP deposition is associated with chondrocyte hypertrophy, CPPD deposition is associated with cellular senescence.

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BCP crystals promote chondrocyte hypertrophic differentiation in OA cartilage by sequestering Wnt3a

Cited by 41 publications

References 56 publications

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

Replicative Verification of Susceptibility Genes Previously Identified from Families with Segregating Developmental Dysplasia of the Hip

Chondrocytes From Osteoarthritic and Chondrocalcinosis Cartilage Represent Different Phenotypes

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