PTH Induces Systemically Administered Mesenchymal Stem Cells to Migrate to and Regenerate Spine Injuries

Sheyn, Dmitriy; Shapiro, Galina; Tawackoli, Wafa; Jun, Douk Soo; Koh, Young-Do; Kang, Kyu-Bok; Su, Susan; Da, Xiaoyu; Ben‐David, Shiran; Bez, Maxim; Yalon, Eran; Antebi, Ben; Avalos, Pablo; Stern, Tomer; Zelzer, Elazar; Schwarz, Edward M.; Gazit, Zulma; Pelled, Gadi; Bae, Hyun; Gazit, Dan

doi:10.1038/mt.2015.211

Cited by 47 publications

(48 citation statements)

References 55 publications

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“…Given the major challenges in treating fracture nonunions and critical bone defects, the experimental and clinical evidence supporting the use of rPTH as a potential adjuvant therapy has been met with great enthusiasm. (4)(5)(6)(7)(8)(9)(10)(11)(12) Although the original rationale for this treatment was based on its well-established effects on bone formation, it is now clear that rPTH has several non-anabolic effects that can transition scarful allograft healing toward the scarless healing observed in autografts. (2,23) Most notably, rPTH inhibits arteriogenesis, mast cells, and fibrosis during structural allograft healing.…”

Section: Discussionmentioning

confidence: 99%

Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model

Zhang

Wang

Chang

et al. 2017

Journal of Bone and Mineral Research

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Investigations of teriparatide (rPTH) as a potential treatment for critical defects have demonstrated the predicted anabolic effects on bone formation, and significant non-anabolic effects on healing via undefined mechanisms. Specifically, studies in murine models of structural allograft healing demonstrated that rPTH treatment increased angiogenesis (vessels <30μm), and decreased arteriogenesis (>30 μm) and mast cell numbers, which lead to decreased fibrosis and accelerated healing. To better understand these non-anabolic effects, we interrogated osteogenesis, vasculogenesis and mast cell accumulation in mice randomized to placebo (saline), rPTH (20μg/kg/2days), or the mast cell inhibitor sodium cromolyn (SC) (24μg/kg/2days), via longitudinal micro-CT and multiphoton laser scanning microscopy (MPLSM), in a critical calvaria defect model. Micro-CT demonstrated that SC significantly increased defect window closure and new bone volume versus placebo (p<0.05), although these effects were not as great as rPTH. Interestingly, both rPTH and SC has similar inhibitory effects on arteriogenesis versus placebo (p<0.05) without affecting total vascular volume. MPLSM time course studies in untreated mice revealed that large numbers of mast cells were detected 1 day post-op (43 +/− 17), peaked at 6 days (76 +/− 6), and were still present in the critical defect at the end of the experiment on day 30 (20 +/− 12). In contrast, angiogenesis was not observed until day 4, and functional vessels were first observed on 6 days, demonstrating that mast cell accumulation precedes vasculogenesis. To confirm a direct role of mast cells on osteogenesis and vasculogenesis, we demonstrated that specific diphtheria toxin-α deletion in Mcpt5-Cre-iDTR mice results in similar affects as SC treatment in WT mice. Collectively, these findings demonstrate that mast cells inhibit bone defect healing by stimulating arteriogenesis associated with fibrotic scaring, and that an efficacious non-anabolic effect of rPTH therapy on bone repair is suppression of arteriogenesis and fibrosis secondary to mast cell inhibition.

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Section: Discussionmentioning

confidence: 99%

Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model

Zhang

Wang

Chang

et al. 2017

Journal of Bone and Mineral Research

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“…Eight weeks postoperatively, the animals were euthanized and their tibiae were harvested for ex vivo, high-resolution μCT (vivaCT 40; SCANCO Medical AG), as previously described (63). Microtomographic slices were acquired using an x-ray tube with a 55-kVp (kilovolt peak) potential and reconstructed at a vox-el size of 35 μm.…”

Section: Methodsmentioning

confidence: 99%

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs

et al. 2017

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More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro–computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchy-mal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation.

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“…Four weeks of PTH treatment in mice examining differences in low dose/high frequency (3 μg/kg, 3 times/day), low dose/low frequency (9 μg/kg, once/day), high dose/high frequency (9 μg/kg, 3 times/day), and high dose/low frequency (27 μg/kg, once/day) indicated high dose and/or high frequency treatment increased callus bone volume but did not have a significant impact on biomechanical recovery whereas low dose/low‐frequency therapy resulted in a lesser increase in callus bone volume but significant increases in biomechanical recovery measures . Likewise, studies by Sheyn et al indicate 0.4 μg/kg was more successful in accelerating and maintaining repair of bone defects in ostoportic rats than higher doses. Current FDA approved treatment is 20 μg/day (0.3–0.5 μg/kg) for up to 2 years when used in humans for treatment of osteoporosis.…”

Section: Efficacy Of Systemic Pth For Bone Regeneration and Defect Rementioning

confidence: 99%

“…PTH also has been shown to increase proliferation of bone marrow stem cells and facilitate homing to sites of therapeutic need . In both athymic rats and pigs PTH significantly enhanced mesenchymal stem cell (MSC) migration to the lumbar region (location of cylindrical drill defects in two vertebral bodies) where they differentiated into bone forming cells . There also is evidence for a synergistic effect of treatment with exogenous MSCs and PTH concomitantly when used to treat rib defects in athymic rats .…”

Section: Efficacy Of Systemic Pth For Bone Regeneration and Defect Rementioning

confidence: 99%

Parathyroid hormone for bone regeneration

Wojda

Donahue

2018

Journal Orthopaedic Research

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Delayed healing and/or non-union occur in approximately 5-10% of the fractures that occur annually in the United States. Segmental bone loss increases the probability of non-union. Though grafting can be an effective treatment for segmental bone loss, autografting is limited for large defects since a limited amount of bone is available for harvest. Parathyroid hormone (PTH) is a key regulator of calcium homeostasis in the body and plays an important role in bone metabolism. Presently PTH is FDA approved for use as an anabolic treatment for osteoporosis. The anabolic effect PTH has on bone has led to research on its use for bone regeneration applications. Numerous studies in animal models have indicated enhanced fracture healing as a result of once daily injections of PTH. Similarly, in a human case study, non-union persisted despite treatment attempts with internal fixation, external fixation, and autograft in combination with BMP-7, until off label use of PTH1-84 was utilized. Use of a biomaterial scaffold to locally deliver PTH to a defect site has also been shown to improve bone formation and healing around dental implants in dogs and drill defects in sheep. Thus, PTH may be used to promote bone regeneration and provide an alternative to autograft and BMP for the treatment of large segmental defects and non-unions. This review briefly summarizes the unmet clinical need for improved bone regeneration techniques and how PTH may help fill that void by both systemically and locally delivered PTH for bone regeneration applications. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2586-2594, 2018.

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PTH Induces Systemically Administered Mesenchymal Stem Cells to Migrate to and Regenerate Spine Injuries

Cited by 47 publications

References 55 publications

Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model

Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs

Parathyroid hormone for bone regeneration

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