- Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital, Wuhan University, Wuhan 430071, P.R.China;
Parathyroid hormone (PTH) exerts multiple effects such as regulating bone remodeling, promoting angiogenesis, etc., and it is an active factor with great application potential for bone repair. In recent years, with the development of scaffold material loading strategies and parathyroid hormone-related peptides (PTHrPs), in situ loading of PTH or PTHrPs on scaffold materials to promote bone defect healing gradually becomes possible. Based on the current status and challenges of intermittent PTH (iPTH) for bone tissue engineering, the review summarizes the in-situ application strategies of PTH and the construction of PTHrPs as well as current problems and further directions in this field, with a view to propel the clinical application of scaffold materials loaded with PTH or PTHrPs in situ.
Citation： HAO Zhuowen, LI Jingfeng. Local administration of parathyroid hormone and parathyroid hormone-related peptides for bone tissue engineering. Journal of Biomedical Engineering, 2021, 38(5): 1028-1034. doi: 10.7507/1001-5515.202104045 Copy
| 1. | Chen C H, Hsu E L, Stupp S I. Supramolecular self-assembling peptides to deliver bone morphogenetic proteins for skeletal regeneration. Bone, 2020, 141: 115565. |
| 2. | Yu F, Xia W. The epidemiology of osteoporosis, associated fragility fractures, and management gap in China. Arch Osteoporos, 2019, 14(1): 32. |
| 3. | Cheng C, Wentworth K, Shoback D M. New frontiers in osteoporosis therapy. Annu Rev Med, 2020, 71: 277-288. |
| 4. | Compston J E, McClung M R, Leslie W D. Osteoporosis. Lancet, 2019, 393: 364-376. |
| 5. | Fang B, Qiu P, Xia C, et al. Extracellular matrix scaffold crosslinked with vancomycin for multifunctional antibacterial bone infection therapy. Biomaterials, 2021, 268: 120603. |
| 6. | Tan W, Gao C, Feng P, et al. Dual-functional scaffolds of poly(L-lactic acid)/nanohydroxyapatite encapsulated with metformin: Simultaneous enhancement of bone repair and bone tumor inhibition. Mater Sci Eng C Mater Biol Appl, 2021, 120: 111592. |
| 7. | Cui L, Xiang S, Chen D, et al. A novel tissue-engineered bone graft composed of silicon-substituted calcium phosphate, autogenous fine particulate bone powder and BMSCs promotes posterolateral spinal fusion in rabbits. J Orthop Translat, 2021, 26: 151-161. |
| 8. | Plantz M A, Hsu W K. Recent research advances in biologic bone graft materials for spine surgery. Curr Rev Musculoskelet Med, 2020, 13(3): 318-325. |
| 9. | Safari B, Aghanejad A, Rshangar L, et al. Osteogenic effects of the bioactive small molecules and minerals in the scaffold-based bone tissue engineering. Colloids Surf B Biointerfaces, 2021, 198: 111462. |
| 10. | Halloran D, Durbano H W, Nohe A. Bone morphogenetic protein-2 in development and bone homeostasis. J Dev Biol, 2020, 8(3): 19. |
| 11. | James A W, Lachaud G, Shen Jia, et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng Part B Rev, 2016, 22(4): 284-297. |
| 12. | Bhattarai H K, Shrestha S, Rokka K, et al. Vitamin D, calcium, parathyroid hormone, and sex steroids in bone health and effects of aging. J Osteoporos, 2020, 2020: 9324505. |
| 13. | Arnold A, Dennison E, Kovacs C S, et al. Hormonal regulation of biomineralization. Nat Rev Endocrinol, 2021, 17(5): 261-275. |
| 14. | Silva B C, Bilezikian J P. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol, 2015, 22: 41-50. |
| 15. | Wein M N, Kronenberg H M. Regulation of bone remodeling by parathyroid hormone. Cold Spring Harb Perspect Med, 2018, 8(8): a031237. |
| 16. | Wojda S J, Donahue S W. Parathyroid hormone for bone regeneration. J Orthop Res, 2018, 36(10): 2586-2594. |
| 17. | Cohen A, Shiau S, Nair N, et al. Effect of teriparatide on bone remodeling and density in premenopausal idiopathic osteoporosis: a phase II trial. J Clin Endocrinol Metab, 2020, 105(10): e3540-e3556. |
| 18. | Jiang L, Zhang W, Wei L, et al. Early effects of parathyroid hormone on vascularized bone regeneration and implant osseointegration in aged rats. Biomaterials, 2018, 179: 15-28. |
| 19. | Yoshida W, Matsugami D, Murakami T, et al. Combined effects of systemic parathyroid hormone (1-34) and locally delivered neutral self-assembling peptide hydrogel in the treatment of periodontal defects: an experimental in vivo investigation. J Clin Periodontol, 2019, 46(10): 1030-1040. |
| 20. | Pelled G, Lieber R, Avalos P, et al. Teriparatide (recombinant parathyroid hormone 1-34) enhances bone allograft integration in a clinically relevant pig model of segmental mandibulectomy. J Tissue Eng Regen Med, 2020, 14(8): 1037-1049. |
| 21. | Dang Ming, Koh A J, Danciu T, et al. Preprogrammed long-term systemic pulsatile delivery of parathyroid hormone to strengthen bone. Adv Healthc Mater, 2017, 6(3): 1600901. |
| 22. | Dang Ming, Koh A J, Jin X, et al. Local pulsatile PTH delivery regenerates bone defects via enhanced bone remodeling in a cell-free scaffold. Biomaterials, 2017, 114: 1-9. |
| 23. | Yue S, He H, Li B, et al. Hydrogel as a biomaterial for bone tissue engineering: a review. Nanomaterials (Basel), 2020, 10(8): 1511. |
| 24. | Ding X, Zhao H, Li Y, et al. Synthetic peptide hydrogels as 3D scaffolds for tissue engineering. Adv Drug Deliv Rev, 2020, 160: 78-104. |
| 25. | Wojda S J, Marozas I A, Anseth K S, et al. Thiol-ene hydrogels for local delivery of PTH for bone regeneration in critical size defects. J Orthop Res, 2020, 38(3): 536-544. |
| 26. | Wojda S J, Marozas I A, Anseth K S, et al. Impact of release kinetics on efficacy of locally delivered parathyroid hormone for bone regeneration applications. Tissue Eng Part A, 2021, 27(3/4): 246-255. |
| 27. | Arrighi I, Mark S, Alvisi M, et al. Bone healing induced by local delivery of an engineered parathyroid hormone prodrug. Biomaterials, 2009, 30(9): 1763-1771. |
| 28. | Zou Z, Wang L, Zhou Z, et al. Simultaneous incorporation of PTH(1-34) and nano-hydroxyapatite into chitosan/alginate Hydrogels for efficient bone regeneration. Bioact Mater, 2021, 6(6): 1839-1851. |
| 29. | Dubey N, Ferreira J A, Malda J, et al. Extracellular matrix/amorphous magnesium phosphate bioink for 3D bioprinting of craniomaxillofacial bone tissue. ACS Appl Mater Interfaces, 2020, 12(21): 23752-23763. |
| 30. | Singh Y P, Moses J C, Bhardwaj N, et al. Injectable hydrogels: a new paradigm for osteochondral tissue engineering. J Mater Chem B, 2018, 6(35): 5499-5529. |
| 31. | Yu X, Wei M. Preparation and evaluation of parathyroid hormone incorporated CaP coating via a biomimetic method. J Biomed Mater Res B Appl Biomater, 2011, 97(2): 345-354. |
| 32. | Auersvald C M, Santos F R, Nakano M M, et al. The local administration of parathyroid hormone encourages the healing of bone defects in the rat calvaria: micro-computed tomography, histological and histomorphometric evaluation. Arch Oral Biol, 2017, 79: 14-19. |
| 33. | Tao Z S, Zhou W S, Wu X J, et al. Single-dose local administration of parathyroid hormone (1-34, PTH) with β-tricalcium phosphate/collagen (β-TCP/COL) enhances bone defect healing in ovariectomized rats. J Bone Miner Metab, 2019, 37(1): 28-35. |
| 34. | Iwai A, Kajii F, Tanaka H, et al. Bone regeneration by freeze-dried composite of octacalcium phosphate collagen and teriparatide. Oral Dis, 2018, 24(8): 1514-1521. |
| 35. | Kajii F, Iwai A, Tanaka H, et al. Single-dose local administration of teriparatide with a octacalcium phosphate collagen composite enhances bone regeneration in a rodent critical-sized calvarial defect. J Biomed Mater Res B Appl Biomater, 2018, 106(5): 1851-1857. |
| 36. | Matsui K, Kawai T, Ezoe Y, et al. Segmental bone reconstruction by octacalcium phosphate collagen composites with teriparatide. Tissue Eng Part A, 2021, 27(9/10): 561-571. |
| 37. | Neto A S, Fonseca A C, Abrantes J C, et al. Surface functionalization of cuttlefish bone-derived biphasic calcium phosphate scaffolds with polymeric coatings. Mater Sci Eng C Mater Biol Appl, 2019, 105: 110014. |
| 38. | Sutkeviciute I, Clark L J, White A D, et al. PTH/PTHrP receptor signaling, allostery, and structures. Trends Endocrinol Metab, 2019, 30(11): 860-874. |
| 39. | Liang B, Huang J, Xu J, et al. Local delivery of a novel PTHrP via mesoporous bioactive glass scaffolds to improve bone regeneration in a rat posterolateral spinal fusion model. RSC Adv, 2018, 8(22): 12484-12493. |
| 40. | Shen Y F, Huang J H, Wang K Y et al. PTH derivative promotes wound healing via synergistic multicellular stimulating and exosomal activities. Cell Commun Signal, 2020, 18(1): 40. |
| 41. | Wang J, Li J, Yang L, et al. Dose-dependence of PTH-related peptide-1 on the osteogenic induction of MC3T3-E1 cells in vitro. Medicine (Baltimore), 2017, 96(17): e6637. |
| 42. | Wang Y, Wang J, Zheng J, et al. Ectopic osteogenesis by type I collagen loaded with a novel synthesized PTH-related peptide-1 in vivo. J Biomed Mater Res A, 2020, 108(1): 166-177. |
| 43. | Yang L, Huang J, Yang S, et al. Bone regeneration induced by local delivery of a modified PTH-derived peptide from nanohydroxyapatite/chitosan coated true bone ceramics. ACS Biomater Sci Eng, 2018, 4(9): 3246-3258. |
| 44. | Huang J, Lin D, Wei Z, et al. Parathyroid hormone derivative with reduced osteoclastic activity promoted bone regeneration via synergistic bone remodeling and angiogenesis. Small, 2020, 16(6): e1905876. |
| 45. | Ling C, Zhao W, Wang Z, et al. Structure-activity relationships of hydroxyapatite-binding peptides. Langmuir, 2020, 36(10): 2729-2739. |
| 46. | Qiao Y, Liu X, Zhou X, et al. Gelatin templated polypeptide co-cross-linked hydrogel for bone regeneration. Adv Healthc Mater, 2020, 9(1): e1901239. |
| 47. | Tang J, Yan D, Chen L, et al. Enhancement of local bone formation on titanium implants in osteoporotic rats by biomimetic multilayered structures containing parathyroid hormone (PTH)-related protein. Biomed Mater, 2020, 15(4): 045011. |
| 48. | Martin T J, Sims N A, Seeman E. Physiological and pharmacological roles of PTH and PTHrP in bone using their shared receptor, PTH1R. Endocr Rev, 2021, 42(4): 383-406. |
| 49. | Martin T J. Parathyroid hormone-related protein, its regulation of cartilage and bone development, and role in treating bone diseases. Physiol Rev, 2016, 96(3): 831-871. |
| 50. | Ardura J A, Portal-Núñez S, Alonso V, et al. Handling parathormone receptor type 1 in skeletal diseases: realities and expectations of abaloparatide. Trends Endocrinol Metab, 2019, 30(10): 756-766. |
| 51. | Bhattacharyya S, Pal S, Chattopadhyay N. Abaloparatide, the second generation osteoanabolic drug: molecular mechanisms underlying its advantages over the first-in-class teriparatide. Biochem Pharmacol, 2019, 166: 185-191. |
| 52. | Rachner T D, Hofbauer L C, Göbel A, et al. Novel therapies in osteoporosis: PTH-related peptide analogs and inhibitors of sclerostin. J Mol Endocrinol, 2019, 62(2): R145-R154. |
| 53. | Brommage R. New targets and emergent therapies for osteoporosis. Handb Exp Pharmacol, 2020, 262: 451-473. |
| 54. | Ning Z, Tan B, Chen B, et al. Precisely controlled delivery of abaloparatide through injectable hydrogel to promote bone regeneration. Macromol Biosci, 2019, 19(6): e1900020. |
- 1. Chen C H, Hsu E L, Stupp S I. Supramolecular self-assembling peptides to deliver bone morphogenetic proteins for skeletal regeneration. Bone, 2020, 141: 115565.
- 2. Yu F, Xia W. The epidemiology of osteoporosis, associated fragility fractures, and management gap in China. Arch Osteoporos, 2019, 14(1): 32.
- 3. Cheng C, Wentworth K, Shoback D M. New frontiers in osteoporosis therapy. Annu Rev Med, 2020, 71: 277-288.
- 4. Compston J E, McClung M R, Leslie W D. Osteoporosis. Lancet, 2019, 393: 364-376.
- 5. Fang B, Qiu P, Xia C, et al. Extracellular matrix scaffold crosslinked with vancomycin for multifunctional antibacterial bone infection therapy. Biomaterials, 2021, 268: 120603.
- 6. Tan W, Gao C, Feng P, et al. Dual-functional scaffolds of poly(L-lactic acid)/nanohydroxyapatite encapsulated with metformin: Simultaneous enhancement of bone repair and bone tumor inhibition. Mater Sci Eng C Mater Biol Appl, 2021, 120: 111592.
- 7. Cui L, Xiang S, Chen D, et al. A novel tissue-engineered bone graft composed of silicon-substituted calcium phosphate, autogenous fine particulate bone powder and BMSCs promotes posterolateral spinal fusion in rabbits. J Orthop Translat, 2021, 26: 151-161.
- 8. Plantz M A, Hsu W K. Recent research advances in biologic bone graft materials for spine surgery. Curr Rev Musculoskelet Med, 2020, 13(3): 318-325.
- 9. Safari B, Aghanejad A, Rshangar L, et al. Osteogenic effects of the bioactive small molecules and minerals in the scaffold-based bone tissue engineering. Colloids Surf B Biointerfaces, 2021, 198: 111462.
- 10. Halloran D, Durbano H W, Nohe A. Bone morphogenetic protein-2 in development and bone homeostasis. J Dev Biol, 2020, 8(3): 19.
- 11. James A W, Lachaud G, Shen Jia, et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng Part B Rev, 2016, 22(4): 284-297.
- 12. Bhattarai H K, Shrestha S, Rokka K, et al. Vitamin D, calcium, parathyroid hormone, and sex steroids in bone health and effects of aging. J Osteoporos, 2020, 2020: 9324505.
- 13. Arnold A, Dennison E, Kovacs C S, et al. Hormonal regulation of biomineralization. Nat Rev Endocrinol, 2021, 17(5): 261-275.
- 14. Silva B C, Bilezikian J P. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol, 2015, 22: 41-50.
- 15. Wein M N, Kronenberg H M. Regulation of bone remodeling by parathyroid hormone. Cold Spring Harb Perspect Med, 2018, 8(8): a031237.
- 16. Wojda S J, Donahue S W. Parathyroid hormone for bone regeneration. J Orthop Res, 2018, 36(10): 2586-2594.
- 17. Cohen A, Shiau S, Nair N, et al. Effect of teriparatide on bone remodeling and density in premenopausal idiopathic osteoporosis: a phase II trial. J Clin Endocrinol Metab, 2020, 105(10): e3540-e3556.
- 18. Jiang L, Zhang W, Wei L, et al. Early effects of parathyroid hormone on vascularized bone regeneration and implant osseointegration in aged rats. Biomaterials, 2018, 179: 15-28.
- 19. Yoshida W, Matsugami D, Murakami T, et al. Combined effects of systemic parathyroid hormone (1-34) and locally delivered neutral self-assembling peptide hydrogel in the treatment of periodontal defects: an experimental in vivo investigation. J Clin Periodontol, 2019, 46(10): 1030-1040.
- 20. Pelled G, Lieber R, Avalos P, et al. Teriparatide (recombinant parathyroid hormone 1-34) enhances bone allograft integration in a clinically relevant pig model of segmental mandibulectomy. J Tissue Eng Regen Med, 2020, 14(8): 1037-1049.
- 21. Dang Ming, Koh A J, Danciu T, et al. Preprogrammed long-term systemic pulsatile delivery of parathyroid hormone to strengthen bone. Adv Healthc Mater, 2017, 6(3): 1600901.
- 22. Dang Ming, Koh A J, Jin X, et al. Local pulsatile PTH delivery regenerates bone defects via enhanced bone remodeling in a cell-free scaffold. Biomaterials, 2017, 114: 1-9.
- 23. Yue S, He H, Li B, et al. Hydrogel as a biomaterial for bone tissue engineering: a review. Nanomaterials (Basel), 2020, 10(8): 1511.
- 24. Ding X, Zhao H, Li Y, et al. Synthetic peptide hydrogels as 3D scaffolds for tissue engineering. Adv Drug Deliv Rev, 2020, 160: 78-104.
- 25. Wojda S J, Marozas I A, Anseth K S, et al. Thiol-ene hydrogels for local delivery of PTH for bone regeneration in critical size defects. J Orthop Res, 2020, 38(3): 536-544.
- 26. Wojda S J, Marozas I A, Anseth K S, et al. Impact of release kinetics on efficacy of locally delivered parathyroid hormone for bone regeneration applications. Tissue Eng Part A, 2021, 27(3/4): 246-255.
- 27. Arrighi I, Mark S, Alvisi M, et al. Bone healing induced by local delivery of an engineered parathyroid hormone prodrug. Biomaterials, 2009, 30(9): 1763-1771.
- 28. Zou Z, Wang L, Zhou Z, et al. Simultaneous incorporation of PTH(1-34) and nano-hydroxyapatite into chitosan/alginate Hydrogels for efficient bone regeneration. Bioact Mater, 2021, 6(6): 1839-1851.
- 29. Dubey N, Ferreira J A, Malda J, et al. Extracellular matrix/amorphous magnesium phosphate bioink for 3D bioprinting of craniomaxillofacial bone tissue. ACS Appl Mater Interfaces, 2020, 12(21): 23752-23763.
- 30. Singh Y P, Moses J C, Bhardwaj N, et al. Injectable hydrogels: a new paradigm for osteochondral tissue engineering. J Mater Chem B, 2018, 6(35): 5499-5529.
- 31. Yu X, Wei M. Preparation and evaluation of parathyroid hormone incorporated CaP coating via a biomimetic method. J Biomed Mater Res B Appl Biomater, 2011, 97(2): 345-354.
- 32. Auersvald C M, Santos F R, Nakano M M, et al. The local administration of parathyroid hormone encourages the healing of bone defects in the rat calvaria: micro-computed tomography, histological and histomorphometric evaluation. Arch Oral Biol, 2017, 79: 14-19.
- 33. Tao Z S, Zhou W S, Wu X J, et al. Single-dose local administration of parathyroid hormone (1-34, PTH) with β-tricalcium phosphate/collagen (β-TCP/COL) enhances bone defect healing in ovariectomized rats. J Bone Miner Metab, 2019, 37(1): 28-35.
- 34. Iwai A, Kajii F, Tanaka H, et al. Bone regeneration by freeze-dried composite of octacalcium phosphate collagen and teriparatide. Oral Dis, 2018, 24(8): 1514-1521.
- 35. Kajii F, Iwai A, Tanaka H, et al. Single-dose local administration of teriparatide with a octacalcium phosphate collagen composite enhances bone regeneration in a rodent critical-sized calvarial defect. J Biomed Mater Res B Appl Biomater, 2018, 106(5): 1851-1857.
- 36. Matsui K, Kawai T, Ezoe Y, et al. Segmental bone reconstruction by octacalcium phosphate collagen composites with teriparatide. Tissue Eng Part A, 2021, 27(9/10): 561-571.
- 37. Neto A S, Fonseca A C, Abrantes J C, et al. Surface functionalization of cuttlefish bone-derived biphasic calcium phosphate scaffolds with polymeric coatings. Mater Sci Eng C Mater Biol Appl, 2019, 105: 110014.
- 38. Sutkeviciute I, Clark L J, White A D, et al. PTH/PTHrP receptor signaling, allostery, and structures. Trends Endocrinol Metab, 2019, 30(11): 860-874.
- 39. Liang B, Huang J, Xu J, et al. Local delivery of a novel PTHrP via mesoporous bioactive glass scaffolds to improve bone regeneration in a rat posterolateral spinal fusion model. RSC Adv, 2018, 8(22): 12484-12493.
- 40. Shen Y F, Huang J H, Wang K Y et al. PTH derivative promotes wound healing via synergistic multicellular stimulating and exosomal activities. Cell Commun Signal, 2020, 18(1): 40.
- 41. Wang J, Li J, Yang L, et al. Dose-dependence of PTH-related peptide-1 on the osteogenic induction of MC3T3-E1 cells in vitro. Medicine (Baltimore), 2017, 96(17): e6637.
- 42. Wang Y, Wang J, Zheng J, et al. Ectopic osteogenesis by type I collagen loaded with a novel synthesized PTH-related peptide-1 in vivo. J Biomed Mater Res A, 2020, 108(1): 166-177.
- 43. Yang L, Huang J, Yang S, et al. Bone regeneration induced by local delivery of a modified PTH-derived peptide from nanohydroxyapatite/chitosan coated true bone ceramics. ACS Biomater Sci Eng, 2018, 4(9): 3246-3258.
- 44. Huang J, Lin D, Wei Z, et al. Parathyroid hormone derivative with reduced osteoclastic activity promoted bone regeneration via synergistic bone remodeling and angiogenesis. Small, 2020, 16(6): e1905876.
- 45. Ling C, Zhao W, Wang Z, et al. Structure-activity relationships of hydroxyapatite-binding peptides. Langmuir, 2020, 36(10): 2729-2739.
- 46. Qiao Y, Liu X, Zhou X, et al. Gelatin templated polypeptide co-cross-linked hydrogel for bone regeneration. Adv Healthc Mater, 2020, 9(1): e1901239.
- 47. Tang J, Yan D, Chen L, et al. Enhancement of local bone formation on titanium implants in osteoporotic rats by biomimetic multilayered structures containing parathyroid hormone (PTH)-related protein. Biomed Mater, 2020, 15(4): 045011.
- 48. Martin T J, Sims N A, Seeman E. Physiological and pharmacological roles of PTH and PTHrP in bone using their shared receptor, PTH1R. Endocr Rev, 2021, 42(4): 383-406.
- 49. Martin T J. Parathyroid hormone-related protein, its regulation of cartilage and bone development, and role in treating bone diseases. Physiol Rev, 2016, 96(3): 831-871.
- 50. Ardura J A, Portal-Núñez S, Alonso V, et al. Handling parathormone receptor type 1 in skeletal diseases: realities and expectations of abaloparatide. Trends Endocrinol Metab, 2019, 30(10): 756-766.
- 51. Bhattacharyya S, Pal S, Chattopadhyay N. Abaloparatide, the second generation osteoanabolic drug: molecular mechanisms underlying its advantages over the first-in-class teriparatide. Biochem Pharmacol, 2019, 166: 185-191.
- 52. Rachner T D, Hofbauer L C, Göbel A, et al. Novel therapies in osteoporosis: PTH-related peptide analogs and inhibitors of sclerostin. J Mol Endocrinol, 2019, 62(2): R145-R154.
- 53. Brommage R. New targets and emergent therapies for osteoporosis. Handb Exp Pharmacol, 2020, 262: 451-473.
- 54. Ning Z, Tan B, Chen B, et al. Precisely controlled delivery of abaloparatide through injectable hydrogel to promote bone regeneration. Macromol Biosci, 2019, 19(6): e1900020.