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

Abstract

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 (PZ0.0008), BUA (PZ0.005) and SOS (PZ0.001) 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. 158 755-764 European Journal of Endocrinology

Exogenous PTHrP Repairs the Damaged Fracture Healing of PTHrP+/− Mice and Accelerates Fracture Healing of Wild Mice

“…The current study suggests that endogenous PTHrP affects bone BMD and shows that BMD increased after injecting PTHrP at one, two, and four weeks (Figure 1), therefore the PTHrP levels within the bone microenvironment might be critical in influencing bone mass acquisition [25]. Another study supported the conclusions of previous studies, suggesting that PTHrP functions as an anabolic agent to osteoblast [26].…”

“…An experimental study demonstrated that mice with osteoblast-specific deletion of PTHrP exhibited impaired recruitment and increased apoptosis of osteogenic cells resulting in decreased bone formation and premature osteoporosis [25], thus PTHrP would serve as an early and effective identifier of individuals at risk of developing low bone mass and osteoporosis. The current study suggests that endogenous PTHrP affects bone BMD and shows that BMD increased after injecting PTHrP at one, two, and four weeks (Figure 1), therefore the PTHrP levels within the bone microenvironment might be critical in influencing bone mass acquisition [25].…”

Parathyroid hormone and its receptor gene polymorphisms: implications in osteoporosis and in fracture healing

“…Gupta et al [35] studied specific allelic variations in the variable number of tandem repeats (VNTR) region of PTHrP in young Finnish males. This polymorphism in PTHrP is located in intron V, 100-bp downstream of exon VI.…”

“…The human gene encoding PTHR1 located at 3p21-p22 [33][34][35][36][37][38][39] contains three promoters (P1, P2, P3) that control transcription [36,37]. Minigawa et al [38] reported that P3 promoter is GC rich, but it contains an A-rich sequence that includes a polymorphic tetranucleotide repeat (AAAG)n. In (AAAG) n-containing P3 promoter constructs, the size of the AAAG repeats affected promoter activity in osteoblastic cells.…”

Physiologic Actions of PTH I

“…48 Osteoblastic PTHrP may also contribute to the maintenance of skeletal mass by transducing mechanical forces. 49 Finally, in humans, heterozygous loss-of-function mutations in the gene encoding PTHrP are associated with brachydactyly type E and short stature, 50 polymorphisms in the PTHrP gene have been associated with attainment of peak bone mass in young men 51 and specific allelic variants have been associated with reductions in BMD, 52 suggesting that skeletal anabolic activity is also of importance in adult humans.…”