Impairment of the chondrogenic phase of endochondral ossification in vivo by inhibition of cyclooxygenase-2

Janssen, M; Caron, M.M.; Rietbergen, Bert van; Surtel, D.A.; Rhijn, Lodewijk W. van; Welting, T.; Emans, Pieter J.

doi:10.22203/ecm.v034a13

Cited by 21 publications

(20 citation statements)

References 23 publications

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“…Moreover, patients suffering from inflammatory disorders like rheumatoid arthritis (RA) often exhibit delayed fracture healing [2][3][4][5][6][7][8][9][10], or even develop pseudarthrosis [8][9][10]. Additionally, glucocorticoids (GCs) and nonsteroidal anti-inflammatory drugs (NSAIDs), both being in daily clinical use for the treatment of RA, have been reported to hamper bone metabolism and fracture healing [11][12][13][14][15]. Another potent therapeutic agent in the treatment of RA is the anti-inflammatory drug tofacitinib [16].…”

Section: Introductionmentioning

confidence: 99%

Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

Gaber

Brinkman

Pienczikowski

et al. 2020

IJMS

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Both inflammatory diseases like rheumatoid arthritis (RA) and anti-inflammatory treatment of RA with glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs) negatively influence bone metabolism and fracture healing. Janus kinase (JAK) inhibition with tofacitinib has been demonstrated to act as a potent anti-inflammatory therapeutic agent in the treatment of RA, but its impact on the fundamental processes of bone regeneration is currently controversially discussed and at least in part elusive. Therefore, in this study, we aimed to examine the effects of tofacitinib on processes of bone healing focusing on recruitment of human mesenchymal stromal cells (hMSCs) into the inflammatory microenvironment of the fracture gap, chondrogenesis, osteogenesis and osteoclastogenesis. We performed our analyses under conditions of reduced oxygen availability in order to mimic the in vivo situation of the fracture gap most optimal. We demonstrate that tofacitinib dose-dependently promotes the recruitment of hMSCs under hypoxia but inhibits recruitment of hMSCs under normoxia. With regard to the chondrogenic differentiation of hMSCs, we demonstrate that tofacitinib does not inhibit survival at therapeutically relevant doses of 10–100 nM. Moreover, tofacitinib dose-dependently enhances osteogenic differentiation of hMSCs and reduces osteoclast differentiation and activity. We conclude from our data that tofacitinib may influence bone healing by promotion of hMSC recruitment into the hypoxic microenvironment of the fracture gap but does not interfere with the cartilaginous phase of the soft callus phase of fracture healing process. We assume that tofacitinib may promote bone formation and reduce bone resorption, which could in part explain the positive impact of tofacitinib on bone erosions in RA. Thus, we hypothesize that it will be unnecessary to stop this medication in case of fracture and suggest that positive effects on osteoporosis are likely.

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Section: Introductionmentioning

confidence: 99%

Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

Gaber

Brinkman

Pienczikowski

et al. 2020

IJMS

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“…27 However, other studies have shown deregulation of growth plate development by other NSAIDs. 11,24,[28][29][30] This study is the first to show that naproxen (in an equivalent human dosage) influences murine growth plate development, the bone microstructure, cortical bone quality, and tibial and femoral bone length.…”

Section: Altered Bone Characteristics In Naproxen-and Mtx-treated Micementioning

confidence: 77%

“…Our previous studies 11,14,24 determined that COX enzyme activity is involved in regulating the chondrogenic phase of endochondral ossification. Clinically, this is relevant as inhibition of COX enzymes by NSAIDs can result in hampered endochondral ossification.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents

Caron

Rietbergen

Castermans

et al. 2020

Journal Orthopaedic Research

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Restriction of physical growth and development is a known problem in patients with juvenile idiopathic arthritis (JIA). However, the effect of medical treatment for JIA on skeletal growth in affected children has not been properly investigated. We, therefore, hypothesize that naproxen and methotrexate (MTX) affect endochondral ossification and will lead to reduced skeletal development. Treatment of ATDC5 cells, an in vitro model for endochondral ossification, with naproxen or MTX resulted in increased chondrogenic but decreased hypertrophic differentiation. In vivo, healthy growing C57BL/6 mice were treated with naproxen, MTX, or placebo for 10 weeks. At 15 weeks postnatal, both the length of the tibia and the length of the femur were significantly reduced in the naproxen‐ and MTX‐treated mice compared to their controls. Growth plate analysis revealed a significantly thicker proliferative zone, while the hypertrophic zone was significantly thinner in both experimental groups compared to their controls, comparable to the in vitro results. Micro‐computed tomography analysis of the subchondral bone region directly below the growth disc showed significantly altered bone microarchitecture in naproxen and MTX groups. In addition, the involvement of the PTHrP‐Ihh loop in naproxen‐ and MTX‐treated cells was shown. Overall, these results demonstrate that naproxen and MTX have a profound effect on endochondral ossification during growth plate development, abnormal subchondral bone morphology, and reduced bone length. A better understanding of how medication influences the development of the growth plate will improve understanding of endochondral ossification and reveal possibilities to improve the treatment of pediatric patients.

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“…The sample size was calculated and corrected for potential dropout, and eight animals per group were included. The IVB method described by Emans and colleagues was used for ectopically inducing cartilage formation, in which a subperiosteal space is created to induce periosteal endochondral ossification (Emans et al, 2007(Emans et al, , 2010Janssen et al, 2017). In short, the skin was opened over the upper medial side of the tibia, the periosteum was incised just medially of the pes anserinus, leaving the semitendinosus tendon untouched.…”

Section: Animal Studymentioning

confidence: 99%

“…We next determined if Aggrecan or COMP supplementation to the IVB biogel leads is beneficial for the quality of ectopically generated cartilage in the IVB. We used the IVB technique as described earlier (Emans et al, 2010;Janssen et al, 2017) and added either Aggrecan (2% w/v; n = 8 IVBs) or COMP (0.5 mg/ml; n = 8 IVBs) to the agarose biogel, and compared the quality of the cartilage that was generated 14 days after creation of the IVBs with a control group in which only the empty agarose biogel condition was tested (n = 8 IVBs). The wet weight of the formed IVB tissues was not significantly different between the empty agarose group versus the IVBs in which the biogel was supplemented with Aggrecan or COMP ( Figure 3A).…”

Section: Quality Of Ivb Cartilage Generated With Aggrecan or Comp Supmentioning

confidence: 99%

Aggrecan and COMP Improve Periosteal Chondrogenesis by Delaying Chondrocyte Hypertrophic Maturation

Caron

Janssen

Peeters

et al. 2020

Front. Bioeng. Biotechnol.

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The generation of cartilage from progenitor cells for the purpose of cartilage repair is often hampered by hypertrophic differentiation of the engineered cartilaginous tissue caused by endochondral ossification. Since a healthy cartilage matrix contains high amounts of Aggrecan and COMP, we hypothesized that their supplementation in the biogel used in the generation of subperiosteal cartilage mimics the composition of the cartilage extracellular matrix environment, with beneficial properties for the engineered cartilage. Supplementation of COMP or Aggrecan was studied in vitro during chondrogenic differentiation of rabbit periosteum cells and periosteum-derived chondrocytes. Low melting agarose was supplemented with bovine Aggrecan, human recombinant COMP or vehicle and was injected between the bone and periosteum at the upper medial side of the tibia of New Zealand white rabbits. Generated subperiosteal cartilage tissue was analyzed for weight, GAG and DNA content and ALP activity. Key markers of different phases of endochondral ossification were measured by RT-qPCR. For the in vitro experiments, no significant differences in chondrogenic marker expression were detected following COMP or Aggrecan supplementation, while in vivo favorable chondrogenic marker expression was detected. Gene expression levels of hypertrophic markers as well as ALP activity were significantly decreased in the Aggrecan and COMP supplemented conditions compared to controls. The wet weight and GAG content of the in vivo generated subperiosteal cartilage tissue was not significantly different between groups. Data demonstrate the potential of Aggrecan and COMP to favorably influence the subperiosteal microenvironment for the in vivo generation of cartilage for the optimization of cartilage regenerative approaches.

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Impairment of the chondrogenic phase of endochondral ossification in vivo by inhibition of cyclooxygenase-2

Cited by 21 publications

References 23 publications

Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

Evaluation of impaired growth plate development of long bones in skeletally immature mice by antirheumatic agents

Aggrecan and COMP Improve Periosteal Chondrogenesis by Delaying Chondrocyte Hypertrophic Maturation

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