The Fate of Circulating Osteoblasts
http://www.100md.com
《新英格兰医药杂志》
Bone remodeling is a temporally regulated process resulting in the coordinated resorption and formation of skeletal tissue carried out in basic multicellular units throughout life.1 Signals determining the fate, function, and ultimate death of cells of the osteoclast and osteoblast lineages define the populations of cells that resorb and form bone in basic multicellular units. There, osteoblasts appear at sites vacated by osteoclasts, a process called coupling. As resorption by osteoclasts is terminated, the resorptive surface is covered by a thin layer of cement, where osteoblasts assemble to form bone and fill the cavity.2
During growth, two types of bone formation — endochondral and periosteal appositional3 — determine the length and width of the bones. As new bone is formed, it is shaped by means of a process called modeling, which is carried out by uncoupled osteoblasts and osteoclasts. Modeling is determined by mechanical forces and, like remodeling, is increased during the adolescent growth spurt.
Osteoclasts are derived from pluripotential hematopoietic cells, and circulating osteoclast precursor cells contribute to bone resorption. In contrast, osteoblasts are derived from mesenchymal cells present in the skeletal microenvironment, and although osteogenic precursors appear in the circulation, their contribution to bone formation is not documented (Figure 1).1 Since osteoblasts present in the circulation must originate from skeletal tissue, the questions regarding the circulating osteoblast are where they are going and what function they have outside the bone environment.
Figure 1. Bone Modeling and Remodeling by Osteoblasts and Osteoclasts.
The marrow and skeletal tissue are near each other, and it is of interest that the bone lining cell, often considered a preosteoblastic mesenchymal cell or a resting osteoblast, separates osteoblasts and osteoclasts from the marrow. The bone marrow harbors two populations of progenitor stem cells — nonadherent, circulatory, hematopoietic stem cells and osteogenic, adherent, stromal stem cells — that, for the most part, do not circulate.4 However, the presence of circulating osteogenic cells with the capacity to form bone in vivo has been established in rodents and humans. Osteogenic cells could be exported to the circulation by means of sinusoids adjacent to the bone trabeculae.1 In addition, capillaries are present at sites of remodeling, providing another possible route for osteoblasts to reach the circulation.2 The use of this route could raise the possibility that a higher number of osteoblasts would circulate during periods of intense bone modeling or remodeling. Their presence in the circulation would be a simple consequence of this state.
In this issue of the Journal, Eghbali-Fatourechi et al. document the presence of circulating osteoblasts by showing that the circulating cells exhibit gene markers associated with the osteoblast phenotype and are capable of forming mineralized nodules (a marker of osteoblastic differentiation) in culture.5 Subcutaneous implantation of the cells in immunocompromised mice led to the formation of new bone. Some of the findings could have been anticipated, since the presence of osteogenic cells in the systemic circulation of humans has been reported.6 An important finding was the confirmation that nonadherent cells from peripheral blood form a major source of osteogenic cells that have the potential to give rise to bone. Transplantation of marrow cells also gives rise to hematopoietic and osteogenic cells, but whereas hematopoietic cells are irreversibly committed, other stromal cells show plasticity and can differentiate to form adipocytes, chondrocytes, osteoblasts, and other connective-tissue cells.7 An obvious question is What determines the homing of a progenitor stromal cell to a specific target organ and its differentiation toward a specific cell lineage? The answer probably resides in specific cues and signals present in the environment of the local tissue.8 Therefore, if circulating stromal cells have a function, it is probably defined on their arrival at their target tissue.9
In the studies reported by Eghbali-Fatourechi et al., the number of circulating osteoblasts was increased in boys during pubertal growth, a period of intense modeling and remodeling, and correlated with serum levels of insulin-like growth factor (IGF) I and IGF-binding protein 3. A limitation of the research was their measurement of total, instead of free, serum IGF-I levels. Free IGF-I probably offers a better representation of bioavailable IGF-I, since IGF-binding protein 3 and proteolytic activity can modify the fraction of serum IGF-I that is bioavailable.10 The correlation between an increased number of circulatory osteoblasts and serum levels of IGF-I and IGF-binding protein 3 may be coincidental and may not reflect cause and effect. Both IGF-I and IGF-binding protein 3 increase markedly during puberty as a result of higher growth hormone levels and activity, and serum levels of total IGF-I reach a mean concentration of 500 ng per milliliter, of which 0.01 percent is free IGF-I.10
Eghbali-Fatourechi et al. also report a higher number of circulating osteoblasts in three men after recent fractures (fractures induce a high level of bone modeling and remodeling). The axis for growth hormone and IGF-I is not altered in the postfracture period, suggesting that the presence of circulating osteoblasts is related more to the state of bone modeling and remodeling than to IGF-I activity. If this were the case, it would be of interest to quantitate the presence of circulating osteoblasts in other physiological states of high bone remodeling, such as the early postmenopausal years, and correlate the number of circulating cells with the degree of bone remodeling. The growth-hormone–dependent circulating IGF-I plays an important role in skeletal homeostasis and linear growth, but it is important to note that IGF-I synthesized by bone cells could be more relevant to skeletal homeostasis, and its synthesis is controlled by parathyroid hormone.11
IGF-I increases osteocalcin expression and enhances osteoblastic function in vitro and in vivo.12 However, absolute evidence of a direct role of IGF-I in determining the differentiation or fate of osteogenic cells is lacking.13 Therefore, if the increase in circulatory osteoblasts is secondary to the effects of IGF-I, as the authors postulate, an alternate mechanism should be invoked. IGF-I has antiapoptotic activity and may thereby contribute to the maintenance of a pool of mature cells. Bone morphogenetic proteins and Wnt, a family of developmental proteins, induce the differentiation of osteogenic cells, and IGF-I could act indirectly by interacting with bone morphogenetic proteins or Wnt signaling.8 Wnt signaling plays a critical role in cell fate, inducing osteoblastogenesis and suppressing adipogenesis, and in the maintenance of bone mass.14 In osteoblasts, Wnt uses the Wnt–-catenin canonical pathway, and IGF-I stabilizes -catenin with a consequent enhancement of Wnt signaling. Through this mechanism, IGF-I could affect osteoblastic differentiation.
Osteoblasts present in the systemic circulation could be a convenient source of osteogenic cells, facilitating their potential use for the local reconstruction of skeletal defects. Their use for gene therapy will be challenging, since mature cells are difficult to transduce and, furthermore, regulation of specific gene expression will be problematic with current technology.7 After their intravenous administration into irradiated mice, adherent marrow stromal cells from transgenic mice differentiate into mature osteoblasts in skeletal tissue.15 Consequently, it is possible that circulating osteogenic cells return to the skeleton, where they may or may not function as mature osteoblasts. It is also possible that their fate is disposal and death without a function.
In summary, osteogenic cells originating from bone may appear in the circulation, particularly at times of intensive bone remodeling. The homing of circulating osteogenic cells to specific skeletal sites and the signals present in the microenvironment of the bone will determine their ultimate fate and function.
Source Information
From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Conn., and the University of Connecticut School of Medicine, Farmington.
References
Parfitt AM. The bone remodeling compartment: a circulatory function for bone lining cells. J Bone Miner Res 2001;16:1583-1585.
Parfitt AM. The mechanism of coupling: a role for the vasculature. Bone 2000;26:319-323.
Parfitt AM. The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 1994;4:382-398.
Kuznetsov SA, Mankani MH, Gronthos S, Satomura K, Bianco P, Robey PG. Circulating skeletal stem cells. J Cell Biol 2001;153:1133-1140.
Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med 2005;352:1959-1966.
Long MW, Robinson JA, Ashcraft EA, Mann KG. Regulation of human bone marrow-derived osteoprogenitor cells by osteogenic growth factors. J Clin Invest 1995;95:881-887.
Bianco P, Robey PG. Marrow stromal stem cells. J Clin Invest 2000;105:1663-1668.
Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 2003;24:218-235.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-147.
Juul A, Holm K, Kastrup KW, et al. Free insulin-like growth factor I serum levels in 1430 healthy children and adults, and its diagnostic value in patients suspected of growth hormone deficiency. J Clin Endocrinol Metab 1997;82:2497-2502.
Canalis E, Centrella M, Burch W, McCarthy TL. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 1989;83:60-65.
Zhao G, Monier-Faugere MC, Langub MC, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 2000;141:2674-2682.
Thomas T, Gori F, Spelsberg TC, Khosla S, Riggs BL, Conover CA. Response of bipotential human marrow stromal cells to insulin-like growth factors: effect on binding protein production, proliferation, and commitment to osteoblasts and adipocytes. Endocrinology 1999;140:5036-5044.
Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A 2005;102:3324-3329.
Hou Z, Nguyen Q, Frenkel B, et al. Osteoblast-specific gene expression after transplantation of marrow cells: implications for skeletal gene therapy. Proc Natl Acad Sci U S A 1999;96:7294-7299.(Ernesto Canalis, M.D.)
During growth, two types of bone formation — endochondral and periosteal appositional3 — determine the length and width of the bones. As new bone is formed, it is shaped by means of a process called modeling, which is carried out by uncoupled osteoblasts and osteoclasts. Modeling is determined by mechanical forces and, like remodeling, is increased during the adolescent growth spurt.
Osteoclasts are derived from pluripotential hematopoietic cells, and circulating osteoclast precursor cells contribute to bone resorption. In contrast, osteoblasts are derived from mesenchymal cells present in the skeletal microenvironment, and although osteogenic precursors appear in the circulation, their contribution to bone formation is not documented (Figure 1).1 Since osteoblasts present in the circulation must originate from skeletal tissue, the questions regarding the circulating osteoblast are where they are going and what function they have outside the bone environment.
Figure 1. Bone Modeling and Remodeling by Osteoblasts and Osteoclasts.
The marrow and skeletal tissue are near each other, and it is of interest that the bone lining cell, often considered a preosteoblastic mesenchymal cell or a resting osteoblast, separates osteoblasts and osteoclasts from the marrow. The bone marrow harbors two populations of progenitor stem cells — nonadherent, circulatory, hematopoietic stem cells and osteogenic, adherent, stromal stem cells — that, for the most part, do not circulate.4 However, the presence of circulating osteogenic cells with the capacity to form bone in vivo has been established in rodents and humans. Osteogenic cells could be exported to the circulation by means of sinusoids adjacent to the bone trabeculae.1 In addition, capillaries are present at sites of remodeling, providing another possible route for osteoblasts to reach the circulation.2 The use of this route could raise the possibility that a higher number of osteoblasts would circulate during periods of intense bone modeling or remodeling. Their presence in the circulation would be a simple consequence of this state.
In this issue of the Journal, Eghbali-Fatourechi et al. document the presence of circulating osteoblasts by showing that the circulating cells exhibit gene markers associated with the osteoblast phenotype and are capable of forming mineralized nodules (a marker of osteoblastic differentiation) in culture.5 Subcutaneous implantation of the cells in immunocompromised mice led to the formation of new bone. Some of the findings could have been anticipated, since the presence of osteogenic cells in the systemic circulation of humans has been reported.6 An important finding was the confirmation that nonadherent cells from peripheral blood form a major source of osteogenic cells that have the potential to give rise to bone. Transplantation of marrow cells also gives rise to hematopoietic and osteogenic cells, but whereas hematopoietic cells are irreversibly committed, other stromal cells show plasticity and can differentiate to form adipocytes, chondrocytes, osteoblasts, and other connective-tissue cells.7 An obvious question is What determines the homing of a progenitor stromal cell to a specific target organ and its differentiation toward a specific cell lineage? The answer probably resides in specific cues and signals present in the environment of the local tissue.8 Therefore, if circulating stromal cells have a function, it is probably defined on their arrival at their target tissue.9
In the studies reported by Eghbali-Fatourechi et al., the number of circulating osteoblasts was increased in boys during pubertal growth, a period of intense modeling and remodeling, and correlated with serum levels of insulin-like growth factor (IGF) I and IGF-binding protein 3. A limitation of the research was their measurement of total, instead of free, serum IGF-I levels. Free IGF-I probably offers a better representation of bioavailable IGF-I, since IGF-binding protein 3 and proteolytic activity can modify the fraction of serum IGF-I that is bioavailable.10 The correlation between an increased number of circulatory osteoblasts and serum levels of IGF-I and IGF-binding protein 3 may be coincidental and may not reflect cause and effect. Both IGF-I and IGF-binding protein 3 increase markedly during puberty as a result of higher growth hormone levels and activity, and serum levels of total IGF-I reach a mean concentration of 500 ng per milliliter, of which 0.01 percent is free IGF-I.10
Eghbali-Fatourechi et al. also report a higher number of circulating osteoblasts in three men after recent fractures (fractures induce a high level of bone modeling and remodeling). The axis for growth hormone and IGF-I is not altered in the postfracture period, suggesting that the presence of circulating osteoblasts is related more to the state of bone modeling and remodeling than to IGF-I activity. If this were the case, it would be of interest to quantitate the presence of circulating osteoblasts in other physiological states of high bone remodeling, such as the early postmenopausal years, and correlate the number of circulating cells with the degree of bone remodeling. The growth-hormone–dependent circulating IGF-I plays an important role in skeletal homeostasis and linear growth, but it is important to note that IGF-I synthesized by bone cells could be more relevant to skeletal homeostasis, and its synthesis is controlled by parathyroid hormone.11
IGF-I increases osteocalcin expression and enhances osteoblastic function in vitro and in vivo.12 However, absolute evidence of a direct role of IGF-I in determining the differentiation or fate of osteogenic cells is lacking.13 Therefore, if the increase in circulatory osteoblasts is secondary to the effects of IGF-I, as the authors postulate, an alternate mechanism should be invoked. IGF-I has antiapoptotic activity and may thereby contribute to the maintenance of a pool of mature cells. Bone morphogenetic proteins and Wnt, a family of developmental proteins, induce the differentiation of osteogenic cells, and IGF-I could act indirectly by interacting with bone morphogenetic proteins or Wnt signaling.8 Wnt signaling plays a critical role in cell fate, inducing osteoblastogenesis and suppressing adipogenesis, and in the maintenance of bone mass.14 In osteoblasts, Wnt uses the Wnt–-catenin canonical pathway, and IGF-I stabilizes -catenin with a consequent enhancement of Wnt signaling. Through this mechanism, IGF-I could affect osteoblastic differentiation.
Osteoblasts present in the systemic circulation could be a convenient source of osteogenic cells, facilitating their potential use for the local reconstruction of skeletal defects. Their use for gene therapy will be challenging, since mature cells are difficult to transduce and, furthermore, regulation of specific gene expression will be problematic with current technology.7 After their intravenous administration into irradiated mice, adherent marrow stromal cells from transgenic mice differentiate into mature osteoblasts in skeletal tissue.15 Consequently, it is possible that circulating osteogenic cells return to the skeleton, where they may or may not function as mature osteoblasts. It is also possible that their fate is disposal and death without a function.
In summary, osteogenic cells originating from bone may appear in the circulation, particularly at times of intensive bone remodeling. The homing of circulating osteogenic cells to specific skeletal sites and the signals present in the microenvironment of the bone will determine their ultimate fate and function.
Source Information
From the Department of Research, Saint Francis Hospital and Medical Center, Hartford, Conn., and the University of Connecticut School of Medicine, Farmington.
References
Parfitt AM. The bone remodeling compartment: a circulatory function for bone lining cells. J Bone Miner Res 2001;16:1583-1585.
Parfitt AM. The mechanism of coupling: a role for the vasculature. Bone 2000;26:319-323.
Parfitt AM. The two faces of growth: benefits and risks to bone integrity. Osteoporos Int 1994;4:382-398.
Kuznetsov SA, Mankani MH, Gronthos S, Satomura K, Bianco P, Robey PG. Circulating skeletal stem cells. J Cell Biol 2001;153:1133-1140.
Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med 2005;352:1959-1966.
Long MW, Robinson JA, Ashcraft EA, Mann KG. Regulation of human bone marrow-derived osteoprogenitor cells by osteogenic growth factors. J Clin Invest 1995;95:881-887.
Bianco P, Robey PG. Marrow stromal stem cells. J Clin Invest 2000;105:1663-1668.
Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 2003;24:218-235.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-147.
Juul A, Holm K, Kastrup KW, et al. Free insulin-like growth factor I serum levels in 1430 healthy children and adults, and its diagnostic value in patients suspected of growth hormone deficiency. J Clin Endocrinol Metab 1997;82:2497-2502.
Canalis E, Centrella M, Burch W, McCarthy TL. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 1989;83:60-65.
Zhao G, Monier-Faugere MC, Langub MC, et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 2000;141:2674-2682.
Thomas T, Gori F, Spelsberg TC, Khosla S, Riggs BL, Conover CA. Response of bipotential human marrow stromal cells to insulin-like growth factors: effect on binding protein production, proliferation, and commitment to osteoblasts and adipocytes. Endocrinology 1999;140:5036-5044.
Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A 2005;102:3324-3329.
Hou Z, Nguyen Q, Frenkel B, et al. Osteoblast-specific gene expression after transplantation of marrow cells: implications for skeletal gene therapy. Proc Natl Acad Sci U S A 1999;96:7294-7299.(Ernesto Canalis, M.D.)