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Stem Cells. Author manuscript; available in PMC Dec 1, 2011.
Published in final edited form as:
PMCID: PMC3125598
NIHMSID: NIHMS305800

Concise Review: Insights from Normal Bone Remodeling and Stem Cell-Based Therapies for Bone Repair

Abstract

There is growing interest in the use of mesenchymal stem cells for bone repair. Since a major reason for normal bone remodeling is the removal of fatigue microcracks, advances in our understanding of this process may inform approaches to enhancing fracture healing. Increasing evidence now indicates that physiological bone remodeling occurs in close proximity to blood vessels and that these vessels carry perivascular stem cells that differentiate into osteoblasts. Similarly, fracture healing is critically dependent on the ingrowth of blood vessels not only for a nutrient supply, but also for the influx of osteoblasts. A number of animal and human studies have now shown the potential benefit of bone marrow-derived mesenchymal stem cells in enhancing bone repair. However, as in other tissues, the question of whether these cells improve fracture healing directly by differentiating into osteoblasts, or indirectly by secreting paracrine factors that recruit blood vessels and the accompanying perivascular stem cells remains a major unresolved issue. Moreover, CD34+ cells, which are enriched for endothelial/hematopoietic cells, have also shown efficacy in various bone repair models, at least in part due to the induction of angiogenesis and recruitment of host progenitor cells. Thus, mesenchymal and non-mesenchymal stem/progenitor cells are attractive options for bone repair. It is possible that they contribute directly to bone repair, but it is also likely that they express paracrine factors in the appropriate amounts and combinations that promote and sustain the healing process.

Keywords: mesenchymal stem cells, bone, fracture, endothelial progenitor cells, bone remodeling

INTRODUCTION

There has been considerable interest in recent years in the use of mesenchymal stem cells for repair of a number of tissues, including bone. While studies in animal models have demonstrated the potential utility of these cells for skeletal regeneration, a number of questions remain regarding how these cells enhance tissue repair, whether in bone or other organs. Certainly a key unresolved question is whether these cells themselves participate in the repair process by differentiating into osteoblasts or largely enhance tissue repair through the secretion of various growth factors that enhance the differentiation of resident stem cells and/or lead to the recruitment of blood vessels, which may bring with them the appropriate stem cells. Moreover, there is increasing evidence that cells of non-mesenchymal origin (e.g., endothelial progenitor cells) may be able to enhance bone and other tissue regeneration. In this brief review, we first provide an update on recent developments in our understanding of normal bone remodeling, since this process likely serves to repair microcracks that develop in the skeleton as a result of normal skeletal loading forces and thus may provide insights into mechanisms of repair following more dramatic insults, such a fracture. We then summarize the current status of approaches to enhance bone repair using stem/progenitor cells of mesenchymal and non-mesenchymal origin.

POTENTIAL INDICATIONS FOR STEM CELL THERAPY IN BONE FRACTURES AND SKELETAL DEFECTS

Perhaps the greatest need for novel approaches, including stem cell therapy, in enhancing bone repair is in chronic nonunion of fractures. This diagnosis is based on a combination of clinical symptoms and physical findings, including pain and motion at the fracture site along with radiographic evidence of failure of union.1 The incidence of nonunion, which can be as high as 5% to 20%, varies by fracture site and is influenced by a number of fracture characteristics and host factors.1 Nonunions are classified as hypertrophic, oligotrophic, and atrophic.1 Hypertrophic nonunions have adequate vascularity and callus formation, and generally only require appropriate mechanical stabilization with external or internal fixation to heal. However, in oligotrophic or atrophic nonunions, there is minimal or no callus formation with diminished or absent vascularity, and it is these types of nonunions that may benefit most from some form of stem cell therapy. In addition to fracture nonunions, segmental bone defects may also be amenable to stem cell reparative approaches.

NORMAL BONE REMODELING AND MICROCRACK REPAIR

Throughout life, bone is constantly being remodeled in a sequence characterized by removal of old bone by osteoclasts and its replacement by osteoblasts.2 The main reason for this physiologic process is likely the removal of fatigue microcracks that occur throughout the skeleton.2 Figure 1 depicts the basic multicellular unit (BMU) which drives the remodeling process and is comprised of the osteoclasts, osteoblasts, osteocytes, and lining cells. While the existence of the BMU has been established for a long time, less well appreciated was the intimate relationship between the BMU and the vasculature, and it is this relationship present even in normal bone remodeling that is perhaps most relevant to bone repair. The close proximity of the BMU to blood vessels was initially described in work by Burkhardt et al.3 over 20 years ago and analyzed in detail in subsequent studies by Hague and colleagues.4 These investigators demonstrated that the BMU, even in trabecular bone in the axial skeleton, was not directly contiguous to the bone marrow, but rather covered by a “canopy” of cells which likely include bone lining cells and, at least in mice, a unique bone-specific (“osteal”) macrophage.5 These canopy cells are connected to lining cells on the quiescent bone surface which, in turn, are in communication with the osteocytes within the bone matrix.4 Penetrating the canopy of lining cells and presumably serving as a conduit for the cells needed in the BMU are marrow capillaries;4, 6 thus, the work of Hauge et al.4 and subsequent studies by Andersen and colleagues6 highlighted both the closed compartment (or bone remodeling compartment [BRC]) comprising the BMU and the intimate relationship between the BMU and the vasculature. Increasing evidence also suggests that the osteocyte may sense microcracks, mechanical strain, and be responsive to changes in the hormonal milieu (e.g., estrogen deficiency) and essentially “trigger” bone remodeling, perhaps via its communication with the bone lining cell.7, 8 The bone lining cell, in turn, initiates the process of bone resorption,7 attracts the osteoclast, and together with adjoining lining cells, begins to form the roof of the BRC. The subsequent ingrowth of a capillary into the BRC provides the vascular supply for the cells in the BMU and may provide the necessary osteoclasts and subsequently, the osteoblasts that are needed for bone remodeling. Within the BMU, preosteoblastic and perhaps lining cells, which express RANKL,9 control osteoclast formation; in turn, completion of the bone resorption phase is followed by a wave of bone formation, driven, in part, by factors produced by the osteoclast that stimulate osteoblast differentiation and activity10 and/or growth factors released from the bone matrix during the process of bone resorption.11

Figure 1
Schematic of the basic multicellular unit (BMU) within the bone remodeling compartment (BRC) showing the key cells involved in normal bone remodeling, including the osteocytes embedded within bone, osteoclasts, osteoblasts, bone lining cells and, at least ...

Concurrent with this evolving view of normal bone remodeling has been the recent demonstration that the perivascular niche is likely a common stem cell microenvironment for resident mesenchymal stem cells within different tissues, including bone.1214 For example, Sacchetti and colleagues13 showed that MCAM/CD146-expressing subendothelial cells in the human bone marrow stroma were capable, upon transplantation into immunocompromised mice, of not only forming ectopic bone but also of transferring the hematopoietic microenvironment. Thus, a plausible hypothesis that is consistent with both our current understanding of normal bone remodeling and the perivascular location of mesenchymal stem cells is that these progenitor cells enter the BRC with the marrow capillary (Figure 1). Indeed, recent evidence indicates that the presence of the blood vessel associated with the BRC may be a prerequisite for the appearance of osteoblasts within the BRC.6

A feature common to both normal bone remodeling and fracture repair is the requirement for the vasculature. It appears that the initial cartilagenous callus that forms following a fracture does so in the absence of a blood vessel, but the replacement of cartilage by bone only occurs following the penetration of blood vessels into the callus.1214 This was recently elegantly demonstrated by Maes and colleagues,14 who used tamoxifen-inducible transgenic mice bred to Rosa26R-LacZ reporter mice to follow the fates of stage-selective subsets of osteoblast lineage cells during embryonic bone development and adult fracture repair. Both in developing bone and in fracture repair, these investigators found that osteoblast precursor cells intimately associate with invading blood vessels, in pericyte-like fashion. As noted earlier, oligotrophic or atrophic nonunions are characterized by the absence of blood vessels and, at surgery, contain calcified cartilage that has not made the conversion step to bone, presumably due to the failure of the ingrowth of blood vessels and associated lack of appropriate osteoblast progenitor cells.15

In summary, both normal bone remodeling (which serves largely to repair fatigue microcracks in bone) and fracture repair appear to depend critically on blood vessels not only for a nutrient supply but also as a source of the perivascular mesenchymal stem cells that ultimately differentiate into osteoblasts. It is in this context that stem cell therapy (using either mesenchymal or non-mesenchymal cells) for fracture nonunions and possibly other skeletal indications is perhaps best understood and further developed.

USE OF STEM/PROGENITOR CELLS IN BONE REPAIR

While the precise identity and nomenclature for defining mesenchymal stem cells remains in some flux, studies utilizing these cells for bone repair have generally used bone marrow plastic adherent cells as originally identified by Friedenstein and colleagues.16 These plastic-adherent bone marrow cells, which account for 0.01–0.0001% of nucleated marrow cells,17 are characterized by a variety of cell surface markers. They are typically negative for CD34, CD45, CD14, CD11b, CD19, CD79a, and HLA-DR and have been shown to be positive for Stro-1, CD29, CD73, CD90, CD105, CD166, and CD44.18 The use of mesenchymal stem cells for fracture repair has been tested in a number of animal models (see Arthur et al.19 for a detailed review). In contrast to hematopoietic, neuronal, or cardiac regeneration, where administration of stem cells alone appears to provide beneficial effects, skeletal repair generally requires the structural and mechanical support provided by a scaffold19 (e.g., allografts of cancellous bone containing viable adult stem cells and osteoprogenitor cells within the matrix and a demineralized bone component). Thus, Kadiyala et al. used autologous bone marrow-derived mesenchymal stem cells that were expanded in culture, loaded onto ceramic cylinders, and implanted in 8-mm segmental defects in rat femora with successful bone formation eight weeks later.20 This same group then demonstrated bone formation at the segmental defect in adult athymic rats by implantation of human bone marrow-derived mesenchymal stem cells.21 A number of other animal studies done with implantation of autologous bone marrow-derived mesenchymal stem cells using different scaffolds have also resulted in bone regeneration.18, 19 Of interest, a recent study using human mesenchymal stem cells for healing segmental bone defects in rats found that a combination of the stem cells with BMP-7, which is known to induce osteoblastic differentiation, resulted in a better osteoinductive graft than either the mesenchymal stem cells or BMP-7 alone,22 suggesting that combining mesenchymal stem cells with specific growth factors may represent a fruitful approach to pursue. Along these lines, a number of studies have successfully used mesenchymal cells expressing vectors encoding factors, such as BMPs, to enhance bone healing.23, 24

In terms of human studies, the use of culture-expanded osteoprogenitor cells in conjunction with porous hydroxyapatite scaffolds was reported in the treatment of 4 patients with diaphyseal segmental defects ranging in size from 3.0 to 28.3 cm3 in a tibia, a humerus, and two separate ulnar fractures.25, 26 Autologous bone marrow-derived pluripotent mesenchymal stem cells were expanded in vitro and loaded on to 100% hydroxyapatite macroporous ceramic scaffolds. The grafts were seeded with the mesenchymal cells and the fracture defects were stabilized with an external fixator. There was progressive integration of the implants with the surrounding bone, new bone formation inside the bioceramic pores, and vascular ingrowth. A good integration of the implants with the preexisting bone was maintained during all the follow-up periods and no major adverse reactions were observed. Radiography and tomography showed that bone formation was far more prominent over the external surface and within the inner canal of the implants. This could be due to a higher density of loaded cells and/or a better survival of cells within the outermost portions of the bioceramics. The patients all recovered limb function. With time, the implants revealed a progressive appearance of cracks and fissures indicative of some bioceramic disintegration, while bone formation progressed and the implants were completely integrated into the existing bone. In all patients at the last follow-up (6 to 7 years post-surgery), a good integration of the implants was maintained.

In further clinical studies, Hernigou et al.27 demonstrated that percutaneous autologous bone-marrow grafting was a potentially effective and safe method for the treatment of atrophic tibial diaphyseal nonunions. Marrow was aspirated from both anterior iliac crests, concentrated on a cell separator, and then injected into 60 non-infected atrophic nonunions of the tibia. There was a positive correlation between the volume of mineralized callus at four months and the number and concentration of fibroblast colony-forming units in the graft. In the 7 patients who did not achieve union, both the concentration and the total number of stem cells injected were significantly lower than in the patients with osseous union. One potential weakness of the study was the absence of a cohort with a placebo treatment. However, the success of the treatment of fracture nonunion with percutaneous bone-marrow grafting did appear to be dependent on the number and concentration of stem cells available for injection.

Despite the emerging evidence that bone marrow mesenchymal stem cells may have utility in animal models and in humans for skeletal repair, the precise mechanism(s) by which these cells enhance tissue repair and regeneration remain unclear, not only for bone but also for other tissues. For example, Arthur et al.19 found that BrdU-labeled human mesenchymal stem cells which survived and contributed to ectopic bone formation when transplanted subcutaneously into immunocompromised mice exhibited little or no proliferation in vivo, suggesting that expansion of these cells and their subsequent differentiation into osteoblastic cells may have had only a limited contribution to the bone that was formed. In analogous studies examining the use of mesenchymal stem cells in islet cell regeneration, Lee et al.28 demonstrated that intracardiac infusion of human mesenchymal stem cells into diabetic NOD/scid mice resulted in a reduction in blood glucose levels, but this was due to the production of mouse (and not human) insulin resulting from the human mesenchymal stem cell-induced regeneration of endogenous mouse β cells. This has led to the general concept, summarized by Prockop,29 that while tissue repair by mesenchymal stem cells may be mediated to some extent by differentiation and/or transdifferentiation of these cells into specific functional cells (e.g., osteoblasts), a significant (and perhaps major) mechanism by which these cells enhance repair of injured tissues may be through paracrine secretions and cell-to-cell contact. Along these lines, Phinney et al.30 used serial analysis of gene expression to catalog the transcriptome of murine bone marrow mesenchymal stem cells. As shown in Figure 2, this transcriptome reflected the plasticity of these cells in that it included a number of mesenchymal lineage-specific transcripts, suggesting that the population was comprised of cells at varying stages of differentiation. Importantly, however, these mesenchymal stem cells also expressed a variety of transcripts related to cell motility and communication, hematopoiesis, immunity and defense, and neural activities. Of particular interest, given the key role for angiogenesis in both normal skeletal remodeling and fracture repair discussed above, was the expression by these cells of a number of mRNAs encoding proteins with proangiogenic activity, including VEGF-B, cysteine rich protein 61 (Cyr61), and connective tissue growth factor, as well as factors affecting endothelial cell growth and migration, such as angio-associated migratory cell protein, angiopoietin, and hepatoma-derived growth factor. Based on these findings, a logical hypothesis is that in addition to enhancing skeletal repair through differentiation into osteoblastic cells, mesenchymal stem cells likely contribute to the repair process through the secretion of these paracrine factors, particularly proangiogenic factors, that lead to ingrowth of the blood vessel and the associated perivascular stem cells that then differentiate into osteoblastic cells. Defining more precisely these direct and indirect effects of mesenchymal stem cells in bone repair, and indeed, tissue repair and regeneration in general, remains a major challenge in the field of stem cell regenerative therapy.

Figure 2
The transcriptome of murine mesenchymal stem cells reflects their plasticity as well as the varied functions they and their progeny perform in bone marrow. The schematic summarizes the nature of catalogued transcripts in the transcriptome of these cells. ...

To the extent that non-mesenchymal cells may also secrete similar paracrine factors and thereby enhance bone repair, it is perhaps not surprising that studies using endothelial/hematopoietic cells have also reported positive outcomes in fracture repair. Thus, Matsumoto and colleagues used magnetic activated cell sorting to isolate human CD34+ cells, which are enriched for an endothelial/hematopoietic progenitor population, and systemically infused these cells into immunocompromised rats with fracture nonunion due to cauterization of the periosteum.31 These investigators found that functional bone healing, assessed by biomechanical as well as radiological and histological examinations, was significantly enhanced by CD34+ cell transplantation compared to animals infused either with saline or unsorted peripheral blood mononuclear cells. Interestingly, while human CD34+ cells in the fracture callus expressed mRNAs for osteocalcin and type I collagen, suggesting the possible differentiation of these circulating cells into osteoblastic cells,3234 the major effect of the CD34+ cells appeared to be the enhancement of intrinsic angiogenesis followed by bone formation by endogenous mouse osteoblastic cells. This group subsequently reported similar findings following local transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood human CD34+ cells placed in a collagen matrix at the fracture nonunion site.35 Consistent with these studies, Rozen et al.36 implanted cultured endothelial progenitor cells from peripheral blood into sheep harboring a large segmental defect in the tibia and found that while none of 8 sham-treated animals had evidence of bone formation in the bone defect, 6 of 7 autologous endothelial progenitor cell-transplanted sheep showed complete bridging of the defect by 8 to 12 weeks. In a similar study in rats, Atesok et al.37 created a segemental bone defect in the femurs of these animals and treated them either with local implantation of cultured endothelial progenitor cells or no cell treatment. Healing of the segmental defect was evaluated using radiographic, histological, and quantitative micro-computed tomography. At 10 weeks, all of the animals in the endothelial progenitor cell treated group had complete union (7/7), but in the control group none (0/7) achieved union. While these studies used either systemic infusion or local implantation of CD34+ cells, endogenous CD34+ cells can also be mobilized using different methods,38, 39 but these approaches have not yet been applied to healing of skeletal defects.

SUMMARY AND CONCLUSIONS

There is a significant need for novel approaches to treat a number of skeletal conditions, including fracture nonunion and bone defects, and stem/progenitor cell therapy represents an attractive option. While animal and limited human studies have shown efficacy of mesenchymal as well as non-mesenchymal stem or progenitor cells in enhancing bone repair, a better understanding of the mechanisms by which these cells improve skeletal regeneration is clearly needed. If, for example, the major effects of these cells turn out to be indirect (i.e., not via differentiation into osteoblastic cells but due to the secretion of paracrine factors), it may be more efficacious and require overcoming fewer regulatory obstacles to use combinations of these paracrine factors for enhancing bone repair. However, identifying the appropriate combinations of factors that initiate and sustain a repair process over time is challenging. Thus, cell-based regenerative therapy may prove to be the best option to meet individual patient needs because of the inherent ability of these cells to respond to their microenvironment. Whatever the ultimate answers, the study and use of stem/progenitor cells in treating skeletal injuries and diseases promises to remain a fruitful area of investigation and more importantly, of potential benefit to our patients.

Acknowledgments

Funding: This work was supported by NIH Grants AG004875, AG028936, AG031750, and AR048147.

Footnotes

Author contribution:

Sundeep Khosla: Conception and design, manuscript writing, final approval of manuscript.

Jennifer J. Westendorf: Conception and design, manuscript writing, final approval of manuscript.

Ulrike I. Mödder: Conception and design, manuscript writing, final approval of manuscript.

Conflict of interest: None of the authors have a conflict to disclose

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

The authors indicate no potential conflicts of interest.

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