A New Spontaneous Model of Fibrodysplasia Ossificans Progressiva

M.S

are aggressive, solitary, and engage in combat with large, saber-like canines. Perhaps because of the lack of specimens, and especially the lack of material prepared specifically to elucidate this ossified sheath, little work has been done on the ossifiations.
The pelvic region and sheath was described 4 and figured 5 , albeit few details are visible.
It was described as "Unique to tragulids is an ossified plate, derived from an aponeurosis (a membranous sheet of tendon) to which the sacral vertebrae attach 6 .
The osseous sheath is interesting as a unique anatomical feature for artiodactyls, as well as all mammals, but it may also have important medical ramifications as a potential model for the devastating human disease, fibrodysplasia ossificans progressiva (FOP). FOP, first described by Guy Paten in 1692, is a genetic disorder characterized by progressive ossification of tendons, ligaments, fascia, and striated muscle 7,8,9,10 . As opposed to simple calcification or deposition of calcium in crystalline form, these structures are actually composed of bone. The relentlessly progressive and seemingly uncontrollable nature of FOP results in immobilization and wheel chair confinement by age 30 in humans 10,11 .
Heterotopic bone in FOP forms rigid synostoses with the normal skeleton.
Heterotopic refers to occurrence in an unusual part of the body. It shares with normal bone the similar histologic appearance of mature cortical and trabecular organization.
There is no established treatment for FOP 9 and prophylactic efforts have had only limited effect 12,13 . Its rarity in humans precludes any scientific assessment of therapeutic efficacy or even natural history of the disease. A natural animal model would allow clarification of its pathophysiology, natural history, and allow meaningful assessment of therapeutic intervention 14 .
Tragulus provides a useful model for FOP, given its reproducibility and its apparent genetic basis. It only occurs in males and was present in all the adults suitable for observation, including both wild obtained and zoo bred animals. This contrasts with a more sporadic occurrence in cats and pigs of a condition that resembles aspects of The ossifications observed in Tragulus mirror that seen in human FOP, especially that illustrated by the skeleton of Harry Eastlack and as illustrated in a recent cat scan 16,17 .

Mr. Eastlack donated his skeleton, which now resides in the Mütter Museum of The
College of Physicians of Philadelphia, and provides the classic standard for recognition of FOP. The pathology described in previous spontaneous animal models appears to be somewhat different. In cats, muscle masses and calcification in or around muscles has been described, but documentation of full heterotopic ossification seems lacking in most reports. Valentine et al. 18 reported firm enlargement of caudal thigh and gastrocnemius muscles, with 'defined areas of mineralization. Individual muscle fibers (not muscles) were surrounded by abnormal calcium deposits; however, there was no heterotopic bone formation. In contrast, they describe proliferative tissue with many hard, gritty or bony foci 0.1-4 cm in diameter 19 . Norris et al. 20 reported widespread fibrosis and ossification of skeletal muscles, primarily as spicules. However, ossification adjacent to the femur was noted, producing the appearance of a second "femur", complete with a fatty marrow cavity. Most of the observed pathology in this cat was due to calcification, not ossification. 'Mineralized' connective tissue was present as spicules in abdominal musculature and as plaques in the small intestine. Waldron et al. 21  Terminology is a challenge. The term myositis ossificans has been used inappropriately 19 because FOP 'does not involve muscle, is multicentric, often symmetrical, and unrelated to trauma. Myositis ossificans … is a peripheral zone of orderly maturation from fibrous to osseous tissue. Definitions however, are open to question. Whether these spontaneous models represent a different stage of FOP or entirely different diseases remains unclear. The mouse embryonic stem cell chimeric c-Fos model does have heterotopic ossification, but "lack the anatomic specificity seen in the human disease" 15,16 . Neither the cat model or Tragulus fully mirrors human FOP, in part because the latter is often associated with congenital malformations of distal limbs 15,18 . Tragulus however, offers an opportunity to examine experimentally many of the disease's most significant attributes in a mammal that can be bred in captivity, the ossifications occur spontaneously, and are sex related.