Chengdu Foreign Language School, No.35 Baicao Road, 611731,P.R. China

Corresponding Author: Di Wang, Chengdu Foreign Language School, No.35 Baicao Road, 611731,P.R. China. E-mail: april.wang20@cflsap.com.

	ABSTRACT
	INTRODUCTION
	DISCUSSION
	ACKNOWLEDGEMENT
	LIST OF ABBREVIATIONS
	CONFLICTS OF INTEREST
	REFERENCES

	ABSTRACT

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal genetic disease that results in abnormal bone formation (heterotopic ossification) in areas of skeletal muscles and connective tissues. Genetic studies have identified the causative mutations in Activin-like kinase 2 (ALK2), a type I receptor of bone morphogenetic proteins (BMPs). Currently no effective treatments are available for FOP, and the disease is often misdiagnosed for less awareness. It is believed that China has the largest number of FOP patients in the world due to its population. However, most Chinese FOP studies were reported in mandarin, instead of English, the international language of science. In this article, I have identified 126 reported Chinese FOP cases by literature search and analyzed these cases from aspects of disease epidemiology, great toe clinical sign, causative mutations and onset ages. In addition, I summarize the most updated knowledge as well as current ongoing clinical trials in FOP field.

	INTRODUCTION

   Normal bone formation is typically limited to skeletal system and is regulated by a well-balanced bone formation and resorption process. Disruption of this process may lead to heterotopic ossification, namely ectopic bone formation outside of skeleton in non-skeletal tissues. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal genetic disease that results in heterotopic ossification in skeletal muscle and connective tissues, and forms a second “heterotopic skeleton” (1, 2). FOP occurs progressively during lifetime, and most patients die at an average age of 40 years (3). The prevalence of FOP is estimated approximately one in two million population. Given the rarity and less unawareness, nearly 90% of FOP patients worldwide were misdiagnosed (4). The first recurrent heterozygous missense causative mutation (R206H) was discovered in activin A receptor type I (ACVR1), also known as activin receptor-like kinase-2 (ALK-2) in 2006 (5) . Subsequently, additional FOP mutations have been found in ALK2 (6-11), and currently no effective treatments are available for FOP. As China has the world's largest population and FOP is known not to be associated with genders, races, geography and ethnicity (12-14), we would reason that China has approximately 700 FOP patients, the largest number in the world. However, most Chinese FOP studies were reported in Mandarin and lack connection with the recent advance in international FOP research. In this article, I performed literature search and identified 126 FOP cases reported in China. I further summarize the epidemiology, great toe malformation, causative mutations and onset ages of Chinese FOP patients as well as the most updated knowledge and clinical trials in current world-wide FOP studies.

   FOP History

   Medical documentation of FOP dates back to the seventeenth century. In 1648, a FOP case was firstly documented by French physician Guy Patin who wrote “the woman who turned to wood” (15). However, the detailed clinical description of FOP was not reported until almost 100 years later. In 1740, British physician John Freke from Saint Bartholomew’s Hospital recorded a FOP case: “There came a boy of healthy look, and about 14 years of age, to ask of us at the hospital, what should be done to cure him of many large swellings on his back, which began about 3 years since, and have continued to grow as large on many parts as a penny loaf particularly on the left side. They arise from all the vertebrae of the neck and reach down to the of sacrum; they likewise arise from every rib of his body, joining together in all parts of his back, as the ramifications of coral do, they make as it were, a foxed bony pair of bodice” (16). Nevertheless, no official name was given to the FOP disease until 1900s when myositis ossificans progressiva was used to name the disease which means "muscle turns progressively to bone. Later the disease name was changed to FOP by Dr. Victor McKusick of Johns Hopkins University School of Medicine as he found that the heterotopic ossification not only happens on muscle, but also on other soft tissues. In 2006, Dr. Frederick Kaplan at the University of Pennsylvania for the first time reported the causative single gene mutation R206H (one letter out of six billion in the human genome) in ACVR1 gene (5). Later, several other new mutations were identified in ALK2 including L196P, R258S, G325A, G328W, G328E, G328R, R202I, Q207E, G356D, R375P and P197/F198L (a deletion of proline 197 and substitution of phenylalanine 198 with leucine) (6-11). Among all these mutations, the mutation R206H comprises approximately 97% all known FOP worldwide (7). The discovery of genetic mutations governing FOP opens an important avenue to FOP drug development.

   Epidemiology, Great Toes, Onset Ages and Genetic Mutations

   I conducted a thorough search of all the reported FOP cases in China by using both myositis ossificans progressiva and Fibrodysplasia Ossificans Progressiva as key words (both English and their Chinese translations). The search was performed in PubMed and CNKI (the most popularly used and comprehensive Chinese database). My search resulted in identification of 126 well-documented FOP patients in China. The data of those patients were analyzed from three aspects: gender, great toe malformation, onset age and genetic mutations in ALK2.

   In non-Chinese patients, FOP is known not to be associated with genders, races, geography and ethnicity (12-14). Consistent with the non-Chinese FOP patients, in the 126 Chinese FOP patients, my data’s analysis shows that 63 (50%) of patients are female and 63 (50%) are males (Figure 1). In addition, many clinical features are associated with FOP such as thumb malformations, clinodactyly, short broad femoral necks and osteochondromas etc., and the most recognized early clinical feature for FOP is the great toe abnormality. In the reported 126 Chinese FOP patients, 121 patients displayed great toes, and five patients showed none-great toe formation (Table 1). This result indicates that great toes may not be the absolute early clinical sign to diagnose FOP although majority of Chinese FOP patients exhibit great toes. Interestingly, recent study in non-Chinese FOP patients reported similar result (17). In addition, their onset age of clinical signs was about 4.67 years old in 125 patients with reported onset ages.

   The R206H mutation in intracellular domain of ALK2 comprises approximately 97% of all known FOP cases worldwide (7). In the reported 126 Chinese FOP patients, 112 patients had the identified genetic mutations, and the rest of 14 Chinese FOP patients had no genetic information available (Table 2). Among the 112 patients with known genetic information, 110 patients carried the R206H mutation which consists of 98.2% of all known FOP cases in China. The other two FOP patients with known genetic mutations, one carrying R258S mutation and the other exhibiting G356D mutation. These two rare mutations R258S and G356D have been both identified in non-Chinese FOP patients before.

   In summary, epidemiology, great toes, onset age and genetic mutations in Chinese FOP patients are consistent with previous reports in non-Chinese FOP studies.

   Molecular Mechanisms

   BMPs and activins are two sub-members of the transforming growth factor β (TGF-β) superfamily. Both BMPs and activins mediate distinct signaling pathways in a similar way (18, 19). They firstly bind to type II kinase receptors which subsequently phosphorylate type I kinase receptor. The activated type I receptors then phosphorylate Receptor-regulated Smads (R-Smads) (19). Next the R-smads form a complex with Smad4, and translocate into nucleus to regulate their target genes’ transcription (Figure 2). ALK2 is a BMP type I receptor which specifically mediates BMP signaling pathway. In FOP, early reports indicated that the ALK2R206H abnormally activates BMP signaling through two mechanisms: 1) a ligand-independent mechanism in which the mutation R206H induces BMP signaling leakage in a basal condition; 2) a BMP ligand-dependent hyper-responsiveness mechanism in which BMP ligands elevate the normal BMP signaling (1, 13). Nevertheless, recent findings have proved that activin A, a ligand which normally transduces TGF-β signaling, cross-activates BMP signaling pathway through FOP ALK2R206H mutant receptor (20, 21). Currently, the underlying mechanism in which activin A cross-activates BMP signaling remains unknown.

   Current Treatment and Drug Development

   Early diagnosis of FOP may help to slow the progression of the disease by taking cautions to avoid trauma, intramuscular injections, surgeries etc. Since influenza and other viral illnesses may trigger flare-ups as well, minimizing viral infection would also improve life quality of FOP patients. Although effective therapies are not available for FOP, several drugs may be beneficial to suppress flare-ups and relieve pain associated with FOP. For instance, corticosteroids are often used at initiation of acute flare-ups that affect major joints and jaws by reducing the intense inflammation. Right after corticosteroid treatment, nonsteroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen will be used in the duration of the flare-up. The complete medication guideline for the FOP treatment can be found at the International Fibrodysplasia Ossificans Progressiva Association website (https://www.ifopa.org).

   Since abnormal BMP signaling is implicated with heterotopic ossification in FOP, significant efforts have been made to develop potential drugs to block the aberrant BMP signaling. Dorsomorphin (DM) is a small molecule inhibitor of the BMP signaling pathway by targeting ALK2 (22). However, DM also displays significant “off-target” activities such as inhibition of the vascular endothelial growth factor (VEGF) signaling pathway (23). To address this issue, several more-selective BMP signaling inhibitors have been subsequently developed including DMH1 and LDN-193189 (23, 24). Additionally, recent new discovery that activin A abnormally signals BMP signaling in FOP leads to development of activin A antibodies to suppress BMP signaling (20, 21).

   To date, two potential drugs are under clinical trials. Palovarotene, an inhibitor of BMP signaling at Smad level, is the first drug evaluated for FOP clinical therapy. The previous phase 2 trial indicated that the Palovarotene treatment reduced heterotopic ossification volume in FOP patients (https://clinicaltrials.gov/ct2/show/NCT03312634). Recently phase 3 clinical trial of Palovarotene was initiated in October, 2017 and is expected to complete in November, 2020. Furthermore, REGN2477Z, an activin A antibody is currently under phase 2 clinical trial which started in March, 2018 and is expected to end in August, 2020.

View larger version : [in a new window] Figure 1. Comparison of FOP morbidities in Chinese males and females. In the reported 126 Chinese FOP patients, 50% of them are males and 50% are females. This result is accorded with the previous reports that FOP has no gender predilection worldwide.

 

View larger version : [in a new window] Figure 2. The mechanism of BMP and Activin A signaling pathways, and activin A cross-signaling BMP pathway through the mutated FOP ALK2 (mALK2). Both BMP and activin A signal distinct pathways in a similar way (A and B). They normally assemble and bind to a heterotetramer complex consisting of a type II receptor homodimer and a type I receptor homodimer (such as ALK2 for BMP and ALK4/7 for activin A) to transduce signaling via Smad phosphorylation (p-Smad1/5/8 for BMPs and p-Smad2/3 for activin A). (C) In normal circumstance, activin A signals TGF-β pathway. But in FOP, activin A can cross-signal BMP signaling through the mutated ALK2 (mALK2).

	DISCUSSION

   FOP is a rare genetic disorder in which a mutation in ALK2 causes abnormal BMP signaling activation. It is estimated that China has approximately 700 FOP patients, the largest number in the world. Unfortunately, majority of FOP cases in China were reported in mandarin. Here I performed literature search and identified 126 reported FOP cases in China. Epidemiology of Chinese FOP patients, great toes, onset age and causative mutations were analyzed. Consistent with previous reports in other countries, FOP in China has no association with genders, and R206H is a predominant genetic mutation. Furthermore, great toe malformation was previously reported as an early diagnostic approach for FOP. However, recent studies indicated that not all FOP patients exhibit great toe malformation (17), and the similar result was found in Chinese FOP cases. In addition, my data shows that the onset age of Chinese FOP patients is at 4.67 years old in average.

   Currently, no effective treatments are available for FOP, and significant efforts have been made to develop potential drugs. For instance, small molecules ALK2 inhibitors including LDN-193189 and DMH1 have been developed (23, 24). Though these small molecules exhibit inhibitory activities against ALK2, they do not display contrasting selectivity between ALK2 and other subtypes of BMP type I receptor. As each subtype of BMP type I receptor plays different critical biological roles, it is essential to develop more-selective BMP inhibitors that can dramatically distinguish ALK2 from other receptor subtypes.

   Palovarotene was the first potential FOP drug that went into clinical trials. The early clinical outcomes demonstrated that Palovarotene treatment reduced heterotopic ossification volume in FOP patients and further phase 3 clinical trial is under way. Moreover, the recent discovery that activin A, a ligand which normally transduces TGF-β signaling, cross-activates BMP signaling through FOP ALK2R206H mutant receptor opens a new door to develop activin A antibodies to treat FOP. Recently, the activin A antibody REGN2477Z developed by Regeneron INC has initiated phase 2 clinical trial. It is expected that effective therapies will soon be available to FOP patients.

	ACKNOWLEDGEMENT

   The author would like to acknowledge Dr. Jijun Hao for guiding and reading the manuscript.

	LIST OF ABBREVIATIONS

FOP	Fibrodysplasia ossificans progressiva
ALK2	glycine-serine-rich
ACVR1	Activin A receptor type I
BMP	bone morphogenetic protein
BMPRI	BMP type-I receptors
VEGFR-2	vascular endothelial growth factor receptor 2

	CONFLICTS OF INTEREST

   The authors declare that no conflicting interests exist.

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	REFERENCES

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