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A Mutation Affecting the Latency-Associated Peptide of TGFß1 in Camurati-Engelmann Disease Enhances Osteoclast Formation in Vitro

Department of Medicine and Therapeutics (N.W.A.M., H.M., J.C.F., S.H.R., M.H.H.), University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom; Department of Medical Genetics (K.J., W.V.H.), University of Antwerp, 2610 Antwerp, Belgium; and Department of Clinical Chemistry (W.D.F.), University of Liverpool, L69 3GA Liverpool, United Kingdom

Address all correspondence and requests for reprints to: Dr. Miep Helfrich, Department of Medicine and Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, United Kingdom. E-mail: m.helfrich{at}abdn.ac.uk.

Camurati-Engelmann disease (CED) is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. CED is caused by various missense mutations in the TGFB1 gene that encodes TGFß1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFß1. We studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from three related CED patients harboring the R218C mutation, in comparison with one family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold (P < 0.001) and bone resorption approximately 10-fold (P < 0.001) in CED patients, and the increase in osteoclast formation was inhibited by soluble TGFß type II receptor. Total serum TGFß1 levels were similar in affected and unaffected subjects, but concentrations of active TGFß1 in conditioned medium of osteoclast cultures was higher in the three CED patients than in the unaffected family member. We concluded that the R218C mutation increases TGFß1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED.

This work was supported by grants from the Arthritis Research Campaign of the United Kingdom (studentship RO558 to N.W.A.M., fellowship H535 to M.H.H., and ICAC grant RO544 to S.H.R.). K.J. holds a predoctoral research position with the Fonds voor Wetenschappelijk Onderzoek (FWO).

Present address for N.W.A.M.: Department of Craniofacial Development, King’s College, London, United Kingdom.

Present address for H.M.: Department of Comparative and Developmental Genetics, MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.

Abbreviations: BMD, Bone mineral density; CED, Camurati-Engelmann disease; FCS, fetal calf serum; LAP, latency-associated peptide; PBMC, peripheral blood mononuclear cell; RANKL, receptor activator of nuclear factor B ligand; rh, recombinant human; rhTGFß-sRII, recombinant human soluble type II TGFß receptor; VNR, vitronectin receptor.

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