Retinoid-Induced Epiphyseal Plate Closure in Guinea Pigs

STANDEVEN, ANDREW M.; DAVIES, PETER J. A.; CHANDRARATNA, ROSHANTHA A. S.; MADER, DOUGLAS R.; JOHNSON, ALAN T.; THOMAZY, VILMOS A.

doi:10.1093/toxsci/34.1.91

Cited by 16 publications

(18 citation statements)

References 10 publications

(15 reference statements)

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“…6A, second panel; Fig. 6B), as previously observed in response to other retinoid agonists, (36,37) but no other major obvious phenotype was noted. Palovarotene-treated mutants showed markedly reduced HO that was nearly absent in their forelimbs and much reduced in hindlimbs ( Fig.…”

Section: Palovarotene Reduces Spontaneous Ho and Improves Skeletal Masupporting

confidence: 82%

Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation

Chakkalakal

Uchibe

Convente

et al. 2016

Journal of Bone and Mineral Research

145

164

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Fibrodysplasia Ossificans Progressiva (FOP) is a rare and as yet untreatable, genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification (HO) in humans and causes skeletal deformities, movement impairment and premature death. Most FOP patients carry an activating mutation in a BMP type I receptor gene, ACVR1R206H, that promotes ectopic chondrogenesis and osteogenesis and in turn HO. We showed previously that the retinoic acid receptor γ (RARγ) agonist Palovarotene effectively inhibited HO in injury-induced and genetic mouse models of the disease. Here we report that the drug additionally prevents spontaneous HO, using a novel conditional-on knock-in mouse line carrying the human ACVR1R206H mutation for classic FOP. In addition, Palovarotene restored long bone growth, maintained growth plate function, and protected growing mutant neonates when given to lactating mothers. Importantly, Palovarotene maintained joint, limb and body motion, providing clear evidence for its encompassing therapeutic potential as a treatment for FOP.

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Section: Palovarotene Reduces Spontaneous Ho and Improves Skeletal Masupporting

confidence: 82%

Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation

Chakkalakal

Uchibe

Convente

et al. 2016

Journal of Bone and Mineral Research

145

164

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“…Current and proposed treatments for HO, including anti-inflammatory agents, pyrophosphate analogues, ionizing radiation therapy, BMP antagonists, and retinoic acid receptor agonists, all have the undesirable adverse effect of disrupting systemic bone homeostasis and inhibiting fracture repair. (70)(71)(72)(73)(74)(75) In stark contrast to these current or proposed therapies, we have previously reported that plasmin activity is essential for fracture repair and bone homeostasis. (30,39) Future studies are required to identify and investigate the complications and clinical feasibility of reducing a2AP to increase plasmin activity.…”

Section: Discussionmentioning

confidence: 99%

Plasmin Prevents Dystrophic Calcification After Muscle Injury

Mignemi

Yuasa

Baker

et al. 2016

Journal of Bone and Mineral Research

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Extensive or persistent calcium phosphate deposition within soft tissues after severe traumatic injury or major orthopedic surgery can result in pain and loss of joint function. The pathophysiology of soft tissue calcification, including dystrophic calcification and heterotopic ossification (HO), is poorly understood; consequently, current treatments are suboptimal. Here, we show that plasmin protease activity prevents dystrophic calcification within injured skeletal muscle independent of its canonical fibrinolytic function. After muscle injury, dystrophic calcifications either can be resorbed during the process of tissue healing, persist, or become organized into mature bone (HO). Without sufficient plasmin activity, dystrophic calcifications persist after muscle injury and are sufficient to induce HO. Downregulating the primary inhibitor of plasmin (α2-antiplasmin) or treating with pyrophosphate analogues prevents dystrophic calcification and subsequent HO in vivo. Because plasmin also supports bone homeostasis and fracture repair, increasing plasmin activity represents the first pharmacologic strategy to prevent soft tissue calcification without adversely affecting systemic bone physiology or concurrent muscle and bone regeneration. © 2016 American Society for Bone and Mineral Research.

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“…Other factors, such as growth hormone, thyroid hormone, and glucocorticoids appear to affect skeletal maturation in humans (38). In addition, retinoid (41) and warfarin (42) toxicity can cause premature fusion. It is not clear whether these conditions cause ossification directly or indirectly by accelerating growth plate senescence.…”

Section: Fig 2 Effect Of Estrogen Treatment On Mean (ϯSem) Tibial Gmentioning

confidence: 99%

Effects of estrogen on growth plate senescence and epiphyseal fusion

Weise

De-Levi

Barnes

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

270

202

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Estrogen is critical for epiphyseal fusion in both young men and women. In this study, we explored the cellular mechanisms by which estrogen causes this phenomenon. Juvenile ovariectomized female rabbits received either 70 g/kg estradiol cypionate or vehicle i.m. once a week. Growth plates from the proximal tibia, distal tibia, and distal femur were analyzed after 2, 4, 6, or 8 weeks of treatment. In vehicle-treated animals, there was a gradual senescent decline in tibial growth rate, rate of chondrocyte proliferation, growth plate height, number of proliferative chondrocytes, number of hypertrophic chondrocytes, size of terminal hypertrophic chondrocytes, and column density. Estrogen treatment accelerated the senescent decline in all of these parameters. In senescent growth plates, epiphyseal fusion was observed to be an abrupt event in which all remaining chondrocytes were rapidly replaced by bone elements. Fusion occurred when the rate of chondrocyte proliferation approached zero. Estrogen caused this proliferative exhaustion and fusion to occur earlier. Our data suggest that (i) epiphyseal fusion is triggered when the proliferative potential of growth plate chondrocytes is exhausted; and (ii) estrogen does not induce growth plate ossification directly; instead, estrogen accelerates the programmed senescence of the growth plate, thus causing earlier proliferative exhaustion and consequently earlier fusion.

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Retinoid-Induced Epiphyseal Plate Closure in Guinea Pigs

Cited by 16 publications

References 10 publications

Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation

Palovarotene Inhibits Heterotopic Ossification and Maintains Limb Mobility and Growth in Mice With the Human ACVR1R206H Fibrodysplasia Ossificans Progressiva (FOP) Mutation

Plasmin Prevents Dystrophic Calcification After Muscle Injury

Effects of estrogen on growth plate senescence and epiphyseal fusion

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