Activated FGFR3 prevents subchondral bone sclerosis during the development of osteoarthritis in transgenic mice with achondroplasia

Okura, Toshiaki; Matsushita, Masaki; Mishima, Kenichi; Esaki, Ryusaku; Seki, Tomohiro; Ishiguro, Naoki; Kitoh, Hiroshi

doi:10.1002/jor.23608

Cited by 19 publications

(9 citation statements)

References 43 publications

(54 reference statements)

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“…Of note, none of our patients required joint replacement surgery (hips, knees, or shoulders), providing longitudinal evidence that joint degeneration is not a common feature of achondroplasia. This result is consistent with a study of a mouse model of achondroplasia, in which surgically induced arthritis occurred to a lesser extent than in wild‐type mice (Okura et al, 2018).…”

Section: Discussionsupporting

confidence: 91%

Natural history of achondroplasia: A retrospective review of longitudinal clinical data

Okenfuss

Moghaddam

Avins

2020

American J of Med Genetics Pt A

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There are limited data on the longitudinal frequency and severity of the symptoms and complications of achondroplasia. We undertook a retrospective electronic chart review of 114 patients to develop a more thorough understanding of the lifetime impact of achondroplasia. Craniocervical stenosis (involving the foramen magnum with or without cervical vertebrae C1 and/or C2) was noted in nearly 50% of patients with craniovertebral junction imaging; however, corrective decompression surgery was only needed in 6% of patients. No children in our cohort died at 4 years of age or under. Kyphosis was present in most patients but usually resolved in early childhood. Cervical and lumbar stenosis were diagnosed in children and adults while, genu varum, elbow contractures, and radial head dislocations were identified during childhood. Central sleep apnea and obstructive sleep apnea were present in children, while the diagnosis of obstructive sleep apnea was shown to recur in adulthood. Cardiovascular risk factors were present in only 7% of patients. A range of mental health disorders were identified, with most diagnoses being made before 18 years of age. Our data show that achondroplasia has a significant impact on patients' physical health, and complications continue to be reported and require intervention throughout patients' lifetimes. This highlights the need for continuous support beyond pediatric care, by adult care clinicians experienced with managing the long-term complications of achondroplasia.

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Section: Discussionsupporting

confidence: 91%

Natural history of achondroplasia: A retrospective review of longitudinal clinical data

Okenfuss

Moghaddam

Avins

2020

American J of Med Genetics Pt A

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“…The effect of PRMT5 inhibition on experimental OA pathogenesis was assessed in a DMM mouse model. DMM results in cartilage erosion, osteophyte formation, and subchondral bone plate thickening [ 32 , 33 ]; therefore, it serves as a model of OA. Figure 4 a shows that EPZ significantly inhibited cartilage destruction in DMM mice; it also reduced the DMM-induced upregulation of MMP-3, MMP-13, and PRMT5 expression, whereas the downregulation of p-p38 and p-p65 expression were observed in the DMM+EPZ group, implying that EPZ can neutralize the activation of the NF-κB and MAPK pathways induced by DMM (Fig.…”

Section: Resultsmentioning

confidence: 99%

PRMT5 inhibition attenuates cartilage degradation by reducing MAPK and NF-κB signaling

et al. 2020

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Objectives A role for the type II arginine methyltransferase PRMT5 in various human diseases has been identified. In this study, the potential mechanism underlying the involvement of PRMT5 in the pathological process leading to osteoarthritis (OA) was investigated. Methods PRMT5 expression in cartilage tissues from patients with OA and control individuals was assessed by immunohistochemical staining. The regulatory and functional roles of PRMT5 in the chondrocytes of patients with OA and control individuals were determined by western blotting and reverse transcription polymerase chain reaction. The effects of the PRMT5 inhibitor EPZ on interleukin-1β-induced inflammation were examined in the chondrocytes of patients with OA and in the destabilized medial meniscus (DMM) of a mouse model of OA. Results PRMT5 was specifically upregulated in the cartilage of patients with OA. Moreover, adenovirus-mediated overexpression of PRMT5 in human chondrocytes caused cartilage degeneration. This degeneration was induced by elevated expression levels of matrix-degrading enzymes (matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13)) in chondrocytes. The activation of the MAPK and nuclear factor κB signaling pathways was evidenced by elevated levels of p-p65, p-p38, and p-JNK. These effects were attenuated by inhibiting the expression of PRMT5. In the mouse model, EPZ inhibited PRMT5 expression, thus protecting mouse cartilage from DMM-induced OA. Conclusions Our results demonstrate that PRMT5 is a crucial regulator of OA pathogenesis, implying that EPZ has therapeutic value in the treatment of this cartilage-destroying disease.

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“…For example, questions that have not been adequately addressed to date include:What is the pathogenetic mechanism giving rise to varus deformity?How much genu varum is tolerable in those with achondroplasia?What is the prevalence of knee osteoarthritis in adults with achondroplasia, and does it correlate with the severity of varus deformity? Recent animal studies suggest that activation of FGFR3 may confer protection against development of osteoarthritis [295, 296]. If this is true in humans as well, then those with achondroplasia may tolerate more severe bowing without debilitating secondary arthritis than is the case in the general population.What are rational indicators for surgery?At what age is surgery best undertaken?What should be the role of 8-plates in treating bowing?Etc.…”

Section: Natural History and Managementmentioning

confidence: 99%

“…What is the prevalence of knee osteoarthritis in adults with achondroplasia, and does it correlate with the severity of varus deformity? Recent animal studies suggest that activation of FGFR3 may confer protection against development of osteoarthritis [295, 296]. If this is true in humans as well, then those with achondroplasia may tolerate more severe bowing without debilitating secondary arthritis than is the case in the general population.…”

Section: Natural History and Managementmentioning

confidence: 99%

Achondroplasia: a comprehensive clinical review

Pauli¹

2019

Orphanet J Rare Dis

350

374

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Achondroplasia is the most common of the skeletal dysplasias that result in marked short stature (dwarfism). Although its clinical and radiologic phenotype has been described for more than 50 years, there is still a great deal to be learned about the medical issues that arise secondary to this diagnosis, the manner in which these are best diagnosed and addressed, and whether preventive strategies can ameliorate the problems that can compromise the health and well being of affected individuals. This review provides both an updated discussion of the care needs of those with achondroplasia and an exploration of the limits of evidence that is available regarding care recommendations, controversies that are currently present, and the many areas of ignorance that remain.

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Activated FGFR3 prevents subchondral bone sclerosis during the development of osteoarthritis in transgenic mice with achondroplasia

Cited by 19 publications

References 43 publications

Natural history of achondroplasia: A retrospective review of longitudinal clinical data

Natural history of achondroplasia: A retrospective review of longitudinal clinical data

PRMT5 inhibition attenuates cartilage degradation by reducing MAPK and NF-κB signaling

Achondroplasia: a comprehensive clinical review

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