Intermittently Administered Parathyroid Hormone [1–34] Promotes Tendon-Bone Healing in a Rat Model

Abstract

The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1–34] (PTH[1–34]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. Every day, injections of 60 μg PTH[1–34]/kg subcutaneously were given to the PTH group rats (n = 10) for four weeks, and the controls (n = 10) received saline. The tendon-bone healing process was evaluated by micro-CT, biomechanical test, histological and immunohistochemical analyses. The effects of PTH[1–34] on serum chemistry, bone microarchitecture and expression of the PTH receptor (PTH1R) and osteocalcin were determined. Administration of PTH[1–34] significantly increased serum levels of calcium, alkaline phosphatase (AP), osteocalcin and tartrate-resistant acid phosphatase (TRAP). The expression of PTH1R on both osteocytes and chondrocyte-like cells at the tendon-bone interface was increased in the PTH group. PTH[1–34] also enhanced the thickness and microarchitecture of trabecular bone according to the micro-CT analysis. The results imply that systematically intermittent administration of PTH[1–34] promotes tendon-bone healing at an early stage via up-regulated PTH1R. This method may enable a new strategy for the promotion of tendon-bone healing after ACL reconstruction.

Is a Local Administration of Parathyroid Hormone Effective to Tendon‐to‐Bone Healing in a Rat Rotator Cuff Repair Model?

“…PTH plays an important role in the treatment of osteoporosis due to its anabolic effect, and PTH therapy is known to enhance bone formation and improve fracture healing . Many studies have shown that PTH increases chondrocyte recruitment and differentiation, and intermittently administered PTH has been shown to improve trabecular bone thickness and microarchitecture . PTH use can directly stimulate osteocytes and chondrocytes and promote growth factor expression .…”

“…The tendon‐to‐bone repair mechanism is similar to bone healing, which is dependent on the proliferation and differentiation of mesenchymal stem cells, matrix formation, and tissue remodeling . During the tendon–bone healing process, PTH can bind to PTH1R in mesenchymal stem cells and osteoblasts accelerate tendon–bone healing . Chen et al demonstrated that PTH could increase the proliferation of mesenchymal stem cells and affect tendon–bone healing process by regulating the secretion of certain factors from mesenchymal stem cells, osteocytes, or osteoblasts.…”

Lactoferrin and parathyroid hormone are not harmful to primary tenocytes in vitro, but PDGF may be

“…Interestingly, PTH treatment reduced the expression of the chondrocytic genes aggrecan and sox9, suggesting that it may also help in the maintenance of a tenocytic lineage. The clinical correlation between high serum PTH and poor tendon health is likely due to continuous exposure to PTH and increased bone resorbing osteoclast activity at the tendon-bone interface 14,15 , rather than the short or intermittent administration discussed in this paper and the pre-clinical studies published to date [7][8][9] . These results suggest that PTH may have a slight beneficial effect on tendon healing, particularly in the tendon-bone area as pre-clinical studies have suggested.…”

“…However, when taken into context with previously published data, it may have a use in treating tendonbone defects, where tendon, fibrocartilage and bone occur within millimetres. Clinically, hypothyroidism has been linked to musculoskeletal problems in humans 12 , and increased serum PTH is associated with tendon laxity and spontaneous tendon rupture [13][14][15] , although pre-clinical in vivo studies using PTH suggest it may have some benefit in tendon healing [7][8][9] . In our study PTH had no effect on tendon proliferation or collagen production, but did increase the expression of decorin, which plays a role in matrix assembly and could have direct implications on collagen fibrillogenesis.…”

“…Recently there has been a number of small animal studies looking at the use of bone-active factors to improve tendon healing, either in models of flexor tendon injury, or in the more complex tendon-bone defects. Parathyroid hormone (PTH) treatment was shown to increase the expression of key matrix genes in the flexor tendon, but had poor effect on joint mobility 7 , while in both ACL reconstruction and rotator cuff healing, PTH increased the amount of bone present at the tendon-bone interface, and therefore increased total pull-out strength of the repaired defect 8,9 . Peptides derived from lactoferrin, a potent bone anabolic factor, have also been shown to improve the healing outcomes of flexor tendons, by reducing focal adhesions 10,11 .…”