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Variable number of tandem repeats polymorphism in parathyroid hormone-related protein as predictor of peak bone mass in young healthy Finnish males

Osta Biotechnologies Inc., Pointe Claire, Québec, H9A 3H2 Canada¹ Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, F1-00029 Finland² Department of Statistics, University of Turku, Turku, F1-20014 Finland³ Department of Human Genetics, Sir Mortimer B. Davis-Jewish General Hospital, and Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, H3T 1E2 Canada⁴ Calcium Research Laboratory and Department of Medicine, McGill University Health Centre and, McGill University, Montréal, Québec, H3A 1A1 Canada⁵ Department of Medicine, Sir Mortimer B Davis-Jewish General Hospital, and Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, H3T 1E2 Canada

(Correspondence should be addressed to A C Karaplis who is now at Division of Endocrinology, Department of Medicine, Sir Mortimer B Davis-Jewish General Hospital, 3755 Côte Ste Catherine Road, Montréal, Québec, H3T 1E2 Canada; Email: akarapli{at}ldi.jgh.mcgill.ca)

Objective: Mice with osteoblast-specific deletion of parathyroid hormone-related protein (PTHrP) exhibit impaired recruitment and increased apoptosis of osteogenic cells resulting in decreased bone formation and premature osteoporosis. The PTHrP levels within the bone microenvironment are therefore critical in influencing bone mass acquisition. Whether this is applicable in humans has not been established. Here, we studied the association of a variable number of tandem repeats (VNTR) polymorphism in PTHrP with peak bone mass.

Methods: Enrolled in the study were 234 young Finnish males, with median age of 19.6 years (range 18.3–20.6 years). Lifestyle factors, serum bone markers, osteodensitometric measurements (lumbar spine and hip) and calcaneal quantitative ultrasound readings were obtained. The PTHrP VNTR length was determined by the PCR amplification of genomic DNA extracted from peripheral blood and correlated to bone parameters by the multiple regression models.

Results: The presence of at least one 252 bp allele was associated with increased lumbar spine bone mineral density (BMD; P<0.0034), broadband ultrasound attenuation (BUA; P<0.0012) and speed-of-sound (SOS; P<0.0023) measurements. The correlation with increased lumbar spine BMD (P=0.0008), BUA (P=0.005) and SOS (P=0.001) was further strengthened by the pairing of the 252 bp allele with a 460 bp allele in comparison with those without any 252 bp allele. Electrophoretic mobility shift assays were used to illustrate the potential transcriptional functionality of the VNTR sequence.

Conclusion: The results indicate that the PTHrP VNTR sequence likely modulates local PTHrP expression within the skeletal microenvironment and could serve as a diagnostic predictor of peak bone mass acquisition.