title: Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment.
abstract: A stabilized tibia fracture model was used in young (8-week old) and aged (1-year old) mice to define the relative bone regenerative potential and the relative responsiveness of the periosteal progenitor population with aging and PTH 1-34 (PTH) systemic therapy. Bone regeneration was assessed through gene expressions, radiographic imaging, histology/histomorphometry, and biomechanical testing. Radiographs and microCT showed increased calcified callus tissue and enhanced bone healing in young compared to aged mice. A key mechanism involved reduced proliferation, expansion, and differentiation of periosteal progenitor cell populations in aged mice. The experiments showed that PTH increased calcified callus tissue and torsional strength with a greater response in young mice. Histology and quantitative histomorphometry confirmed that PTH increased callus tissue area due primarily to an increase in bone formation, since minimal changes in cartilage and mesenchyme tissue area occurred. Periosteum examined at 3, 5, and 7 days showed that PTH increased cyclin D1 expression, the total number of cells in the periosteum, and width of the periosteal regenerative tissue. Gene expression showed that aging delayed differentiation of both bone and cartilage tissues during fracture healing. PTH resulted in sustained Col10a1 expression consistent with delayed chondrocyte maturation, but otherwise minimally altered cartilage gene expression. In contrast, PTH 1-34 stimulated expression of Runx2 and Osterix, but resulted in reduced Osteocalcin. β-Catenin staining was present in mesenchymal chondroprogenitors and chondrocytes in early fracture healing, but was most intense in osteoblastic cells at later times. PTH increased active β-catenin staining in the osteoblast populations of both young and aged mice, but had a lesser effect in cartilage. Altogether the findings show that reduced fracture healing in aging involves decreased proliferation and differentiation of stem cells lining the bone surface. While PTH 1-34 enhances the proliferation and expansion of the periosteal stem cell population and accelerates bone formation and fracture healing, the effects are proportionately reduced in aged mice compared to young mice. β-Catenin is induced by PTH in early and late fracture healing and is a potential target of PTH 1-34 effects.
authors: Department of Orthopedics, Tokushima University Hospital, Kuramoto, Tokushima, Japan. Electronic address: Kiminori_Yukata@URMC.Rochester.edu.
authors: Kiminori
authors: K
authors: Yukata
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Chao_Xie@URMC.Rochester.edu.
authors: Chao
authors: C
authors: Xie
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: TianFang_Li@URMC.Rochester.edu.
authors: Tian-Fang
authors: TF
authors: Li
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Masahiko_Takahata@URMC.Rochester.edu.
authors: Masahiko
authors: M
authors: Takahata
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
authors: Donna
authors: D
authors: Hoak
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Sirish_Kondabolu@URMC.Rochester.edu.
authors: Sirish
authors: S
authors: Kondabolu
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Xinping_Zhang@URMC.Rochester.edu.
authors: Xinping
authors: X
authors: Zhang
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Hani_Awad@URMC.Rochester.edu.
authors: Hani A
authors: HA
authors: Awad
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Edward_Schwarz@URMC.Rochester.edu.
authors: Edward M
authors: EM
authors: Schwarz
authors: Department of Biostatistics and Computational Biology, University of Rochester, USA. Electronic address: Beck@BST.Rochester.edu.
authors: Christopher A
authors: CA
authors: Beck
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Jennifer_Jonason@URMC.Rochester.edu.
authors: Jennifer H
authors: JH
authors: Jonason
authors: The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA. Electronic address: Regis_OKeefe@URMC.Rochester.edu.
authors: Regis J
authors: RJ
authors: O'Keefe
mesh_terms: D000375:Aging / Q000187:drug effects; D045930:Anabolic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001861:Bone Regeneration / Q000187:drug effects*; D002146:Bony Callus / Q000187:drug effects / Q000473:pathology; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D005260:Female; D017102:Fracture Healing / Q000187:drug effects; D006801:Humans; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000494:pharmacology* / Q000627:therapeutic use; D010521:Periosteum / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013978:Tibial Fractures / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D045930:Anabolic Agents; D010281:Parathyroid Hormone
keywords: Fracture healing; Mesenchymal stem cell; Parathyroid hormone; Periosteum; Wnt-β-catenin signaling