BoneKEy-Osteovision | Commentary

Identification of the gene responsible for sclerosteosis casts new light on the physiology of bone formation



DOI:10.1138/2001022

Sclerosteosis (MIM 269500) is a rare sclerosing bone dysplasia, which predominantly affects the Afrikaner population in South Africa (). The disease was initially considered to be a variant of osteopetrosis (), but subsequent metabolic studies () revealed that the disorder is primarily one of increased bone formation, rather than defective bone resorption. Sclerosteosis is inherited in an autosomal recessive fashion and presents clinically with generalized osteosclerosis, tall stature, facial deformities, and cranial nerve compression syndromes (). Other clinical features include widening of the calvarial bones, radial deviation of the terminal phalanges and dysplastic or absent nails. In some cases, the calvarial abnormalities are so severe as to cause raised intracranial pressure and sudden death as the result of brain stem compression.

Sclerosteosis is similar in phenotype to van Buchem disease, which is also an autosomal recessive sclerosing bone dysplasia that has predominantly been reported in subjects from the Netherlands (). Van Buchem disease tends to be milder than Sclerosteosis, however, and is not associated with syndactyly. The phenotypic overlap between the conditions, coupled with the ancestral links between the Dutch and Afrikaner population, has led to speculation that the two diseases may represent allelic disorders occurring as the result of different mutations in the same gene ().

Progress in defining the molecular basis of these bone dysplasias began with mapping of the van Buchem's disease gene to a 0.7 cM interval on chromosome 17q12-q21 by van Hul and colleagues in 1998 (). Subsequently, the same group mapped Sclerosteosis to the same region of chromosome 17q in 1999 (), fueling speculation that the disorders have a similar molecular basis.

Positional cloning studies by van Hul's group () and an independent group of researchers from South Africa, Italy and the U.S.A. () have now resulted in the identification of mutations in a novel gene termed SOST as the cause of Sclerosteosis. The disease causing mutations were homozygous premature stop codons in 3 families and a homozygous splice site mutation in other individuals which was shown by Brunkow et al. () to reduce production of the SOST mRNA to approximately 10% of the normal level. Surprisingly, neither group found evidence of mutations in the SOST gene itself or in DNA surrounding SOST in van Buchem disease patients. Whilst this raises the possibility that a different, but closely linked gene may be responsible for van Buchem disease, another, and perhaps more likely explanation, would be mutations in cis-acting regulatory sequences upstream or downstream of the SOST gene itself ().

The above work is a major advance in defining the molecular basis of Sclerosteosis and will have an important impact on the genetic management of the condition. Of equal importance are the potential implications for the treatment of diseases characterized by reduced bone mass such as osteoporosis. The fact that these “loss of function” mutations in SOST lead to a progressive increase in bone formation, suggests that SOST plays a key physiological role as a negative regulator of bone formation.

Sequence analysis of SOST indicates that it is a secreted protein, containing a so-called “cysteine-knot” motif (). This was first described in the TGFb superfamily () but has subsequently been found in other proteins such as von Willebrand factor (), members of the connective tissue growth factor family and the so-called DAN family of secreted glycoproteins which have been shown to antagonize BMP signaling (). This raises the possibility that the normal function of SOST is to bind to and antagonize the actions of BMP's, and possibly other target molecules in bone, leading to osteoblast overgrowth and new bone formation. Assuming this to be the case, there is a real possibility that if small molecule antagonists of SOST could be developed, they could act as anabolic agents with clinical potential for increasing bone mass.

Further work will be required to define the molecular mechanisms by which SOST stimulates bone formation and to determine whether distant mutations that alter the regulation of SOST are indeed responsible for van Buchem disease. For the moment however, this exciting breakthrough has uncovered a novel pathway that increases bone mass by negatively regulating osteoblast activity. The discovery of this pathway gives hope that pharmacological antagonists of SOST may increase bone formation and hence be of clinical value in restoring bone mass in patients with established osteoporosis. There is a caveat however; whilst Sclerosteosis patients are protected from osteoporosis as the result of increased bone mass, they also experience adverse effects as the result of bony overgrowth affecting cranial nerve foramina. If new therapeutic agents are developed which increase bone formation by inhibiting SOST, it will be important to ensure that they do not reproduce these undesirable aspects of the Sclerosteosis phenotype.


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