Current insights on the regenerative potential of the periosteum: Molecular, cellular, and endogenous engineering approaches.
ABSTRACT While century old clinical reports document the periosteum's remarkable regenerative capacity, only in the past decade have scientists undertaken mechanistic investigations of its regenerative potential. At a Workshop at the 2012 Annual Meeting of Orthopaedic Research Society, we reviewed the molecular, cellular, and tissue scale approaches to elucidate the mechanisms underlying the periosteum's regenerative potential as well as translational therapies engineering solutions inspired by its remarkable regenerative capacity. The entire population of osteoblasts within periosteum, and at endosteal and trabecular bone surfaces within the bone marrow, derives from the embryonic perichondrium. Periosteal cells contribute more to cartilage and bone formation within the callus during fracture healing than do cells of the bone marrow or endosteum, which do not migrate out of the marrow compartment. Furthermore, a current healing paradigm regards the activation, expansion, and differentiation of periosteal stem/progenitor cells as an essential step in building a template for subsequent neovascularization, bone formation, and remodeling. The periosteum comprises a complex, composite structure, providing a niche for pluripotent cells and a repository for molecular factors that modulate cell behavior. The periosteum's advanced, "smart" material properties change depending on the mechanical, chemical, and biological state of the tissue. Understanding periosteum development, progenitor cell-driven initiation of periosteum's endogenous tissue building capacity, and the complex structure-function relationships of periosteum as an advanced material are important for harnessing and engineering ersatz materials to mimic the periosteum's remarkable regenerative capacity. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1869-1878, 2012.
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ABSTRACT: Although a critical role of COX-2 in bone repair has been established, the mechanism involved remains unclear. During early inflammatory phase of bone healing, COX-2 is produced by the surrounding inflammatory cells as well as bone/cartilage progenitors. Based on the temporal and spatial expression of COX-2 during the early phase of fracture healing, we hypothesize that COX-2 from both sources is critical for progenitor cell activation, proliferation and differentiation. To directly test this we utilized a murine femoral grafting model, in which live segmental grafts from the same strains were transplanted and donor versus host cell involvement in healing was assessed. Specifically, fresh femur cortical bone grafts of 4 mm in length from COX-2(-/-) (KO) mice were transplanted into wild type (WT) mice with the same sized segmental defect in femurs. Similarly, grafts from WT were transplanted into the defects in KO mice. As controls, transplantations between wild types, and transplantations between KO were also performed. Histologic analyses showed that WT-to-WT transplantation resulted in normal endochondral bone healing as evidenced by markedly induction of neovascularization and periosteal bone formation on donor graft. In contrast, transplantation of KO graft into KO host led to 96% reduction of bone formation and near elimination of donor cell-initiated periosteal bone formation. Similarly, transplantation of WT graft into a KO host resulted in 87% reduction of bone formation (n=8, p>0.05), indicating that KO host impaired WT donor progenitor cell expansion and differentiation. When a KO graft was transplanted into WT host, KO donor periosteal cell-initiated endochondral bone formation was restored. Histomorphometric analyses demonstrated 10-fold increase in bone formation and 3-fold increase in cartilage formation compared to KO-to-KO transplantation (n=8, p<0.05), suggesting that COX-2 deficient donor cells were capable to differentiate and form bone when placed in a WT host. Taken together, our data strongly suggest that COX-2 is critical for initiation of periosteal cortical bone healing. The early induction of COX-2 constitutes a crucial host-healing environment for activation and differentiation of donor periosteal progenitors. Elimination of COX-2 at the early stage of healing could lead to detrimental effects on periosteal progenitor cell-initiated cortical bone repair.Bone 08/2008; 43(6):1075-83. · 3.82 Impact Factor
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ABSTRACT: The fibrous periosteum forms an intermediary between muscle and ligament forces and the underlying osteoblastic tissue, thus the mechanical properties of the periosteum are critical to understanding osteogenic stimuli. Regional and directional variation in periosteal properties may contribute to the biomechanical regulation of growth in some bones. Periostea of the pig mandibular body, zygomatic arch and metacarpal were loaded to failure under continuous tension. Each tissue type was tested in both the long-axis and transverse orientation. Stiffness, peak stress and peak strain were compared between orientations and among regions. Within the zygomatic periosteum there was little indication of regional difference, and neither zygomatic nor mandibular periosteum showed directional differences. The metacarpal periosteum showed a directional effect only in peak strain, which was greater longitudinally than transversely. There were striking differences, however, among the periostea of the three bones. The zygomatic arch periosteum was the stiffest tissue (91.7+/-30.5 MPa) and showed the highest strength (12.3+/-4.6 MPa). The metacarpal periosteum demonstrated slightly lower stiffness and strength (84.7+/-35.1 and 11.3+/-5.3 MPa), and peak strains in zygomatic and metacarpal periostea were similarly high (17.7+/-3.7 and 17.9+/-3.7 MPa, respectively). The periosteum of the mandibular body was the most deformable tissue (63.0+/-25.4 MPa), with the lowest-peak strain (15.6+/-3.0 MPa) and the least strength (8.2+/-4.1 MPa). These results correspond with those of previous work in long bones, in that periosteum interfacing with ligament or muscle (e.g. zygomatic, metacarpal) demonstrates greater stiffness and strength than periosteum adjacent to loose connective tissue (e.g. mandibular body). Therefore, the degree to which the periosteal tissue serves as a functional interface between bone and muscle is reflected in the different failure properties of periostea from different bones. The structural fortification of the zygomatic arch periosteum relative to other periosteal tissues suggests a role for the periosteum in stabilizing the zygomatic arch-muscle functional complex. On the other hand, the similar failure properties of zygomatic and squamosal periostea from the zygomatic arch mean that the differential growth of these bones cannot be attributed to mechanical stimuli intrinsic to the periosteal tissue.Archives of Oral Biology 11/2002; 47(10):733-41. · 1.55 Impact Factor
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ABSTRACT: Periosteum plays a key role in bone repair through activation of residing stem and/or progenitor cells. The molecular signals regulating differentiation and expansion of periosteal stem cells during early repair are poorly understood. Understanding the molecular basis for initiation and completion of bone healing is vital for the success of bone-tissue engineering and regeneration therapy for impaired bone healing. We established a live-bone-graft transplantation model that allows us to quantitatively evaluate the fate of the periosteal cells and cell-initiated endochondral bone healing with use of a transgenic and knockout mouse model. By combining this live-bone-graft transplantation method with a tamoxifen-inducible CreER-mediated gene recombination model (R26CreER), we developed a novel approach to efficiently delete genes in periosteal cells during the initiation of skeletal repair. This approach allows us to use floxed mice to examine the function of genes whose germline deletion results in lethality during development. Successful bone repair and regeneration therapies require a deeper understanding of the signals and signaling pathways that are critical for the morphogenesis of the repair tissues. Early lethality in genetically manipulated mice prohibits an understanding of the function of genes in the adult repair process. Our current approach overcomes this encumbrance and enables examination of gene function in a time-dependent and repair-tissue-specific manner.The Journal of Bone and Joint Surgery 03/2008; 90 Suppl 1:9-13. · 3.23 Impact Factor