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New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis

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Abstract

Functional, biochemical and genetic studies have over the past decade identified many causative genes in the osteoclast diseases osteopetrosis and Paget's disease of bone. Here, we outline all osteoclast diseases and their genetic associations and then focus specifically on those diseases caused by mutations in the critical osteoclast molecule Receptor Activator of Nuclear factor Kappa B (RANK). Both loss and gain-of-function mutations have been found in humans leading to osteopetrosis and high bone turnover phenotypes, respectively. Osteopetrosis-associated RANK mutations are widely distributed over the RANK molecule. It is likely that some negatively affect ligand binding, whereas others preclude appropriate association of RANK with downstream signalling molecules. In the Paget-like disorders, familial expansile osteolysis, early onset Paget's disease and expansile skeletal hyperphosphatasia, heterozygous insertion mutations are found in the RANK signal peptide. These prevent signal peptide cleavage, trapping the protein translated from the mutated allele in the endoplasmic reticulum. Whole animal studies replicate the hyperactive osteoclast phenotype associated with these disorders and present only with heterozygous expression of the mutation, suggesting an as yet unexplained effect of the mutant allele on normal RANK function. We discuss the cell biological studies and animal models that help us to understand the nature of these different RANK defects and describe how careful dissection of these conditions can help understand critical pathways in osteoclast development and function. We highlight areas that require further study, particularly in light of the pharmacological interest in targeting the RANK signalling pathway to treat diseases caused by excessive bone resorption.

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Acknowledgement

Work of the authors in this field has received support from the arthritis research campaign (now Arthritis Research UK) grants 17440, F0548 and 13630, the Paget Foundation, the Chief Scientist Office of the Scottish Executive (grant CZB/4/495) and the Cunningham Trust, St. Andrews, Scotland. We are grateful to Colin Steward and Fraser Coxon for helpful comments on this manuscript.

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  1. Bone and Musculoskeletal Research Programme, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, AB25 2ZD, Aberdeen, UK

    J. C. Crockett, D. J. Mellis, D. I. Scott & M. H. Helfrich

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  1. J. C. Crockett
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  2. D. J. Mellis
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  3. D. I. Scott
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  4. M. H. Helfrich
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Correspondence to J. C. Crockett.

Additional information

While this review was going to press, a study was published by Albagha et al (Nature Genetics, published online May 2010) demonstrating the association of SNPs on chromosome 18q21, close to the TNFRSF11a locus, with late onset Paget’s Disease in patients without SQSTM1 mutations. This highlights RANK as an additional susceptibility gene for development of late-onset Paget’s disease.

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Crockett, J.C., Mellis, D.J., Scott, D.I. et al. New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis. Osteoporos Int 22, 1–20 (2011). https://doi.org/10.1007/s00198-010-1272-8

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