Association between intermittent administration of parathyroid hormone 1-34 and ectopic calcification in rats

Introduction

Ectopic calcification is pathologic deposition of minerals within soft tissues as dental pulp or periodontal ligaments (PDL)^1,2. Pulpal ectopic calcification may manifest as generalized, linear calcification, or as circumscribed calcification (also known as pulp stones or denticles). Pulp stones can be seen free within the pulp tissues, partially associated with dentin wall or completely embedded in dentin. They may manifest as false concentric calcification or true pulp stones³. The etiology of pulp calcification may be idiopathic⁴, although it may also be associated with pulp injury or degeneration⁵, orthodontic or physical forces^6–8 or chemical stimuli^9,10. Its incidence tends to increase with age^3,11.

Parathyroid hormone (PTH) is a naturally occurring hormone, important for calcium homeostasis^12,13. Its level in the blood dictates its effect on the skeletal system, with bone catabolic effect upon chronic increase in PTH level associated with hyperparathyroidism^13,14 and bone anabolic effect upon administration of small intermittent dosage^15,16. PTH secreted by the parathyroid gland (native PTH) is a polypeptide chain composed of 84 amino acids (PTH 1-84). While PTH 1–34, is a fragment of PTH molecule “synthetised through recombinant DNA technology using a strain of Escherichia coli bacteria”^17,18. Intermittent PTH 1–34 administration, owing to its bone anabolic effect, is successfully used for the management of osteoporosis^19–22. Its bone anabolic effect has been linked to elevated osteoblast differentiation, number and activity^23–29.

Methods

This research was conducted as a part of a study examining the effect of PTH 1–34 on microarchitecture of alveolar process of osteoporotic rats.

Results

Upon histological examination of the Forteo group specimens, six rats showed normal pulp and periodontal ligaments with no ectopic calcifications, while ectopic calcifications were detected in three specimens (Dataset 1)³³. Where true pulp stone with pre-dentin and dentin surrounding a central cavity lined by cells was detected in one specimen (Figure 1a). Another specimen showed the presence of intra-pulpal calcified structure with entrapped cells (Figure 1b). Meanwhile, one specimen displayed the presence of intra-periodontal bone-like calcified structure with entrapped cells (Figure 1c). On the other hand, no ectopic calcification was perceived in the control group specimens (Dataset 1)³³, which showed normal pulp and periodontal ligaments (n=9) (Figure 1d).

Figure 1. Light microscope images of the Forteo-treated group.

(a) A true pulp stone with dentin, pre dentin and central cavity lined by cells (original magnification, x100 (left) and x400 (right)). (b) Intrapulpal calcification with entrapped cells (original magnification, x100 (left) and x400 (right)). (c) Intra-periodontal ectopic calcification with entrapped cells surrounded with disorganized periodontal ligaments (original magnification, x400). (d) Light microscope image of the control group showing normal pulp and periodontal ligaments with no ectopic calcification (original magnification x 100).

Discussion

Despite the fact that PTH 1–34 can successfully lower blood calcium level, and prevent vascular calcification³⁴, in the current work, PTH 1–34 was associated with ectopic calcifications within the pulp and PDL, while none was observed in the control group specimens.

Guimaraes et al. observed increased dentin deposition rate and elevated level of serum alkaline phosphatase in PTH 1–34 treated rats³⁵. In a subsequent research, Guimaraes et al. elucidated that PTH 1–34 can regulate odontoblast like cells via protein kinase A- and protein kinase C-dependent pathways, with increases in odontoblast-like cells proliferation upon short PTH exposure and increases in their apoptosis upon longer exposure³⁶.

Wang et al. demonstrated the ability of PTH to induce human PDL stem cells to differentiate into osteoblasts, which was associated with increased alkaline phosphatase activity and increased mineralization capacity³⁷. Moreover, Li et al. described the ability of PTH 1–34 to induce the formation of calcified nodule in cementoblast cell line, which was attributed to the ability of the drug to increase cementoblast activity, alkaline phosphatase level and subsequently calcification³⁸.

The stimulatory effect of PTH 1–34 on odontoblast, cementoblast and osteoblasts function can help explain the findings of the current research.

Data availability

Dataset 1. Images captured from each mouse in each group not shown in Figure 1.DOI: https://doi.org/10.5256/f1000research.16298.d218523³³.