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Volume 347:210-212 July 18, 2002 Number 3
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Editorial-NEJM

Genetic Control of Bone Remodeling � Insights from a Rare Disease

 

Over the past decade, we have learned a great deal about how skeletal development and remodeling are controlled.1 Some of our knowledge has been derived from genetic analysis of diseases in humans, whereas other important information has come from targeting mutations in mice. In some instances, the two approaches have complemented each other, as occurred in the identification of core binding factor 1 as a major regulator of osteoblast differentiation in mice2,3,4 and the nearly simultaneous demonstration of the mutation in one allele of the gene for core binding factor 1 as the cause of human cleidocranial dysplasia and the murine equivalent.4,5 Earlier this year two groups reported that the same gain-of-function mutation in the gene encoding the low-density lipoprotein receptor�related protein 5 (LRP5) resulted in an autosomal dominant, striking increase in bone mass (a high-bone-density phenotype).6,7 Loss-of-function mutations in LRP5 had previously been identified in the osteoporosis�pseudoglioma syndrome.8 The skeletal phenotype in that disorder, however, is the opposite of the high-bone-density phenotype, yet similar to the phenotype in mice with homozygous deletion of both Lrp5 alleles.9

In this issue of the Journal, using a candidate-gene approach, Whyte et al.10 report that homozygous deletion of the gene on chromosome 8q24.2 encoding osteoprotegerin, member 11B of the superfamily of tumor necrosis factor receptors (TNFRSF11B), leads to a devastating disease marked by skeletal deformities. Affected members of two families had a similar disorder characterized by excessive bone remodeling.

The first description of osteoprotegerin appeared only five years ago.11 Simonet et al. identified osteoprotegerin as a possible novel member of the superfamily of tumor necrosis factor receptors on the basis of sequence homology using complementary DNA (cDNA) from fetal-rat intestine. When the patterns of expression of osteoprotegerin in murine tissues did not reveal sufficient clues about its function, transgenic mice were created in which the cDNA encoding rat osteoprotegerin was expressed under the control of the apolipoprotein E gene promoter and its associated liver-specific enhancer. The mice expressing the transgene superficially appeared no different from their littermates, but radiographic screening showed a dramatic increase in bone density, characteristic of osteopetrosis. Subsequently, Simonet et al.11 demonstrated that recombinant osteoprotegerin blocked osteoclastogenesis in vitro and in vivo and protected mice from bone loss induced by ovariectomy.

Osteoprotegerin has subsequently been shown to function as a decoy receptor for osteoclast differentiation factor and to prevent its interaction with its receptor (receptor activator of nuclear factor-B, or RANK) on osteoclast precursors and mature osteoclasts (Figure 1). Interestingly, an inhibitor of osteoclastogenesis referred to as OCIF had been purified at about the time osteoprotegerin was discovered,12 and when OCIF was cloned a year later,13 it turned out to be identical to osteoprotegerin. As predicted from these studies, targeted loss-of-function mutations in the mouse osteoprotegerin gene results in bone loss associated with a high rate of bone turnover.14



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 		 Figure 1. Differentiation and Activation of Osteoclasts.

Exposure of marrow stromal cells and osteoblasts to substances such as prostaglandin E2, parathyroid hormone, and 1,25-dihydroxyvitamin D stimulates the expression of osteoclast differentiation factor, a transmembrane protein. When these stimulated mesenchymal cells contact osteoclast precursors, cells of hematopoietic origin, they bind to the receptor activator of nuclear factor-B (RANK) on the surface of the osteoclast precursor through osteoclast differentiation factor. Once macrophage colony-stimulating factor binds to its receptor, the precursor cell matures into a functioning osteoclast. To activate bone resorption, osteoclast differentiation factor binds to RANK on the differentiated osteoclasts. Osteoprotegerin is the product of a gene distinct from RANK that inhibits the differentiation of osteoclasts by binding to osteoclast differentiation factor as a decoy and preventing the binding of this factor with its ligand. Other local factors, such as tumor necrosis factor , also have a role in the differentiation and activation of osteoclasts.

 
 
Whyte et al. referred to the disease they described as "juvenile Paget's disease," but it is also called hereditary hyperphosphatasia and hyperostosis corticalis deformans juvenilis. Our nomenclature lags behind the biologic and the genetic advances, but hyperostosis corticalis deformans juvenilis may be a more appropriate name, since the disease is not Paget's disease and is not a primary disorder of alkaline phosphatase regulation. In fact, Paget's disease of bone in adults15 bears only superficial resemblance to the disorder described here by Whyte et al. As was emphasized more than 50 years ago by Albright and Reifenstein16 in their analysis of the pathologic and pathophysiological aspects of Paget's disease of bone, the disease is focal rather than diffuse and always spares some bones or even parts of a bone. Histologically, the diagnostic mosaic pattern of faceted units of lamellar bone is not seen in the juvenile form of the disease. There is familial clustering of Paget's disease of bone in adults, and it had been assumed that genetic as well as environmental factors have a role in pathogenesis. There was increased interest in this area after activating mutations in the TNFRSF11A gene on chromosome 18q21�22 that encodes RANK were identified in another lytic bone disorder, familial expansile osteolysis.17 Mutations in the RANK and osteopro-tegerin genes that could cause Paget's disease of bone, however, have been ruled out in a large number of patients.18 Nevertheless, linkage has recently been shown in a large pedigree to a region adjacent to and excluding TNFRSF11A on chromosome 18q23. This chromosomal region may harbor another susceptibility gene.19 Susceptibility has also been linked to regions on chromosomes 2, 5, 6, and 10.18,20

In other bone diseases characterized by excessive osteoclastic resorption, such as Paget's disease of bone or postmenopausal osteoporosis, pharmacologic suppression of bone resorption (e.g., with calcitonin or bisphosphonates) is followed by a decrease in bone formation. As a result, in patients with Paget's disease of bone, the disordered bone structure that includes woven bone is converted to more normal lamellar bone.15 Successful treatment of hyperostosis corticalis deformans juvenilis with calcitonin, first reported in 1972 by Woodhouse et al.,21 also results in radiographic improvement and a decrease in the markers of bone formation (e.g., a decrease in the levels of alkaline phosphatase in serum) and resorption. Indeed, calcitonin therapy was beneficial in the patients described by Whyte et al.10 Such observations further support the concept that the increased and abnormal bone formation is secondary to the excessive resorption of bone and justify elimination of the term "familial hyperphosphatasia."

The demonstration of mutations in TNFRSF11B in a rare skeletal disorder, together with the observation that these mutations lead to the uncontrolled differentiation and function of osteoclasts, represents another milestone in our understanding of molecular mechanisms that govern skeletal remodeling. Such insights into rare genetic diseases will further the development of agents useful in the treatment of common disorders.

 


Stephen M. Krane, M.D.
Massachusetts General Hospital
Charlestown, MA 02129

References

 

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