MOLECULAR BASIS OF OSTEOGENESIS IMPERFECTA

The bone is a very important structure of the human body. It forms the skeleton, which provide the support and protection for the entire body and its vital organs. Any defect of the structure of the bone can lead to deleterious consequences that can be lethal in some occasions. The bone can be diseased either congenitally or in acquired mode. One of the congenital bone disorders is "osteogenesis imperfecta", which is an inheritable disorder that presents with different degree of manifestation. Different aspects of this rare disorder are discussed here, in this paper.

Definition:
As a terminology, osteogenesis imperfecta means: imperfect bone formation (1). This disorder comprises a group of heterogeneous rare genetic disorders of type I collagen2 that affects bone and connective tissues3. It is also know as "brittle bone disease" due to the fact that the bone is abnormally fragile and has a tendency to be fractured from a minimal trauma, or even without apparent causes (4, 5). Apart from bone fragility, there are numerous clinical features that characterize osteogenesis imperfecta, which are: thin skin, blue sclerae, dentinogenesis imperfecta, joint laxity and progressive deafness(3, 6).

The classification that is used for osteogenesis imperfecta was put by Sillence in 1979 (9). It is based mainly on the clinical features and the mode of inheritance of the disease. It classifies the disease into four main types which are: OI type I, OI type II, OI type III and OI type IV2, (4, 8). Both types I and IV are further subclassified into type IA, type IB, type IVA and type IVB according to the presence or absence of dentinogenesis imperfecta (7, 8). However, some cases cannot be classified because they express criteria of different classes (6, 9). There are distinct molecular and biochemical disorders within each class (7, 8). The Sillence classification, with additional criteria, is shown the following table.

Type:	Severity:	Bone Fragility:	Growth Impairment:	Clinical Features: Blue Sclera	Clinical Features: Dentinogenesis imperfecta:	Clinical Features: Deafness	Inheritance:
IA	mild to..	mild, late	little	yes	absent	some	AD, sporadic
IB	moderate	fractures	*	*	present	50%	new mutations
II	very severe (stillbirth, early neonatal death	extreme (lethal) perinatal fractures; marked long bone deformity	*	yes	some	__	new dominant mutations, parentral mosaicsim, AR
III	severe	antenatal fractures; progressive deformity	severe	blue at birth, normal in adults	common	common	new dominant mutations, AR
IV A	mild to ...	Brittle bones;	May...	pale blue in	absent	some	AD,
IV B	moderate	mild to moderate bone deformity	occur	early childhood, normal in older children	present	*	sporadic new mutations

Investigation:
It is not that easy to diagnose osteogenesis imperfecta due to the fact that most physicians are not familiar with such disorders. However, there are some investigation techniques that can enable to diagnose this disorder. The first technique is radiological imaging that shows deformities, especially in OI type II and III, as a result of intrauterine fractures that healed. However, still in types I and IV the bones have normal appearance. Despite this, skull x-rays have an extreme importance because they show wide sutures with excess wormian bone islands that are small, irregular in shape and at least are ten in number. This method confirms the diagnosis of osteogenesis imperfecta and best-shown in Town's and lateral views (3, 7).

Collagen:
The collagens, whose defects are responsible for IO, are class of fibrous proteins that have structural functions in the body. They have chemical and structural similarities, while they are products of different genes on several chromosomes. There are thirteen distinct types of collagen that are registered into two major classes: those that form banded fibrills and fibers, and those that do not (4, 10, 12). The different types of collagen are shown in the following table (4).

A. Structure of Collagen:
The collagen molecule is made up of three polypeptides known as alpha chains. These chains coiled around one another to form triple helix. The hydrogen bonds are responsible for holding the helical conformation. The amino acids sequence is the main determinant of the alpha chain structure, which contains about 1000 amino acids. The variation of their sequence result in forming alpha chains of the same size and different properties. These alpha chains coil around each other to form different types of collagen that are located in different types of tissue (table 2). (4, 10, 12)
Regarding the amino acid sequence of the alpha-chain, glycine is the most abundant type. It is found in every third position, forming the third of the total amino acid content. The importance of this is that the glycine is the smallest amino acid and that give it the ability to fit into the restricted space where the three chains of the triple helix come in close to each other. The main scheme of amino acid sequence is (-Gly-X-Y) where X is frequently proline and Y is often hydroxyproline or hydroxylysine ( 4, 10-12)

B. Biosynthesis of Collagen:
The collagen genes are transcribed into mRNA that is further translated into prepro-alpha polypeptide chains in the rough endoplasmic reticulum through the ribosomes. These chains contain about 100 extra amino acids of specific sequence at their N-terminal which form a signal indicates that the fate of the chains is to leave the cell. This signal sequence is cleaved in the rough endoplasmic reticulum resulting in the formation of pro-alpha-chain. Then, a hydroxylation takes place for a group of selected proline and lysine residues at the Y position as a posttraslational modification. These hydroxylations are enzymatic process through proline hydroxylase and lysyl hydroxylase actions. They require molecular oxygen and reducing agent such as vitamin C. The hydroxylation is important for the cross-linking process. Furthermore, glycosylation with glucose or galactose are taking place for selected hydroxylysine residues. After these modifications, pro-alpha-chains converted into procollagen with a central triple helix and extension terminal propeptides of non-helical amino- and carboxyl- terminals with disulfide bonds. The procollagen then moves to Golgi apparatus to be packed into the secretory vesicles that release their contents from the cell into the extracellular space by the process of exocytosis. The terminal propeptides are removed extracellularly to release the triple-helix collagen molecule. The triple-helices assembly to form overlapping fibrillar array. The enzyme lysyl oxidase acts on this array to form covalent cross-links, which is essential for collagen stability.(10) Collagen needs to be degraded in response to tissues' growth and injury. This process is accomplished by extracellular collagenases that cleave the intact and stable fibers into smaller fragments.(10, 11)

Collagen Genes:
There are eighteen genes for collagen that encode for thirteen different types of collagen. This diversity is due to the variety of functions that the various types of collagen perform.

A. Mode of Inheritance:
The mode of inheritance of OI is mainly dominant, but could be recessive or result from new mutations. If only one parent has a single faulty gene that dominates the corresponding normal gene, and passes this abnormal gene to one or more of his/her children, so the type of inheritance is dominant. On the other hand, if the both parents carry a copy of the harmful gene, and both pass these defective copies to the child, so it is recessively inherited. However, affected children are born to parents who are totally normal. Here, the mutation is present in the reproductive cells of the parents.(13)

B. Mutations:
In OI, the most important collagen is type I, which its helix consists of two pro alpha1 chains and one pro alpha2 chain [alpha1(I)]2alpha2(I). The genes encoding for these two types of chains are located on chromosome 17 and 7 respectively. There are about 100 mutations that are responsible for OI that occur on these genes. Types of mutations are substitutions, deletion, splicing and frame-shifts. Although these types of mutations occur in different sites in the gene, they produce the same phenotype. The main type is the substitution that leads to changing the obligatory glycine to another amino acid, mostly cystine. This accounts mainly for about 75% of all types of mutations. The mutation causes a quantitative or qualitative defects in collagen I synthesis. Qualitatively, the defective gene could direct cell to make an altered collagen protein. However, quantitatively, the altered gene directs a cell to produce lesser amount of normal collagen. The quantitative defects lead to a mild type of disease (type I OI) while the qualitative defects lead to a lethal form (type II, III and IV OI).(2, 4, 6, 9, 13)

Management:
At the mean time, there is no cure for OI. So, the management of the disease is only aimed at preventing deformities and relieving the symptoms.(3, 5, 9)

A. Drug Therapy:
Different types of drugs were tried in OI, but none of them has an appreciated effect on the disease. Examples of these drugs are calcium, anabolic steroids, vitamin C, calcitonin, fluoride and bisphosphonates.(7) Recently, several types of bisphosphonates showed apparently good results.(9)

B. Surgical Treatment:
Orthopedical surgery is appeared to be essential to correct deformity and prevent further fractures. Intramedullary rodding is the major method and it could be essential for correcting deformity, stabilizing bone and restoring function. It is a procedure in which metal rods are inserted intramedullary in the long bones. There are two types of rodding: extensible and closed. This procedure is mostly helpful for children but not for adults and the early intervention is found to be much effective. Rodding is mostly done for the lower extremities, but occasionally it is done for humerus for correcting deformities. It is difficult for the forearm, so it is done there very rarely.(5-7)
Due to the need of repeated surgeries, the patients have to spend a considerable amount of time immobilized. However, immobilization should be reduced to the minimal need, so osteopenia do not develop. There are different ways of immobilization, including plaster cast, fiberglass cast, bracing, splinting and traction.(7, 14)

C. Pain Management:
While the pain is a great aspect, relieving it is an important issue in managing OI. There are different methods to approach such mission. There are physical, psychological and medical therapies. Heat and ice, transcutatneous electrical nerve stimulation (TENS), exercise or physical therapy, acupuncture and acupressure, and massage therapy are types of physical therapy. Psychological therapy includes relaxation training, biofeedback, visual imagery or distraction, hypnosis, and individual or family therapy. The medication is the most effective method in reliving pain. There are different types of mediations, each of which has its own limitations. Aspirin, ibuprofen, naprosyn sodium and acetaminophen are over-the-counter pain relievers. Other non-steroidal anti-inflammatory drugs (NSAIDs) are used. Topical pain relievers are also used in a form of creams that applied directly on the area of the pain. Narcotics can be used for pain relieving, but they have the disadvantage of crossing blood-brain barrier and producing mental problems and lead to addiction. Antidepressants can also be used for patients who suffer from chronic depression. They improve depression as well as relieving or reducing the amount of pain a person feels. Last method is nerve blockers. These numb the nerve and surrounding tissues and eliminate the sensation of pain.(15)

D. Rehabilitation:
The rehabilitation is important. In OI children, it mainly focuses on two domains: impairment and functional limitation domains. The major goal in the impairment domain is to improve the joint motion and the muscular strength, while in functional limitation one is to improve ambulation and functional ability. Gerber and colleagues concluded after a study on OI type III and IV children that "a comprehensive rehabilitation program combined with long bone leg bracing with surgery on the femur improved functional activity while maintaining an acceptable level of risk for fracture". Sillence showed that the major goal of rehabilitation for OI type I and II children is exercise and community walking, while OI type III and IV children's goal is household or community walking.(6)

Conclusion:
Osteogenesis imperfecta is a skeletal disorder of remarkable clinical variability characterized by bone fragility caused by quantitative and qualitative defects in collage I synthesis. The collagen disorder cannot be treated. Rehabilitation may be indicated to optimize functional ability and, if possible, walking capacity. Disease-related clinical and functional characteristics should guide treatment strategies. Early surgical intervention may be indicated to stabilize the long bones in order to optimize functional ability and walking capacity.

Bibliography:
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[5] http://www.oif.org/tier2/fastfact.htm
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[9] http://www.phys.tue.nl/oife/oimain_uk.htm
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[13] http://www.oif.org/tier2/genetics.htm
[14] http://www.oif.org/tier2/fracture.htm
[15] http://.oif.org/tier2/pain.htm

Type:	Composition:	Distribution:
I	[alpha 1 (I)]2 alpha 2 (I)	skin, tendon, bone, cornea, blood vessels
II	[alpha 1(II)]3	cartilage, intervertebral discs, vitreous body
III	[alpha 1(III)]3	fetal skin, cardiovascular system, reticular fibers, blood vessels
IV	[alpha 1(IV)]2 alpha 2(IV)	basement membrane
V	[alpha 1(V)]2 alpha 2(V)	placenta, skin