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The making of a bone in blood vessels: From the soft shell to the hard bone
co m m e nt a r y
see original article on page 574
The making of a bone in blood vessels: From the soft shell to the hard bone M Fukagawa1 and JJ Kazama2 Vascular calcification, particularly of the medial layer of arteries, is one of the key determinants of survival in patients with chronic kidney disease. This abnormality is not merely a simple process of precipitation of calcium and phosphate but also includes several mechanisms similar to those of bone formation within the vessel wall. Kidney International (2007) 72, 533–534. doi:10.1038/sj.ki.5002440
Vascular calcification is a major abnormality of mineral and bone metabolism in chronic kidney disease (CKD)1 and is one of the major determinants of the risk of cardiovascular events and survival in patients with CKD. 2 In these patients, calcification develops not only in the intima, but also in the media of arteries, where it is known as Monckeberg’s medial sclerosis. 3 As for the pathogenesis, it has recently been well accepted that vascular calcification is not a simple process of precipitation of supersaturated calcium phosphate4 but also includes several mechanisms similar to those of bone formation in situ, such as expression of the osteoblast differentiation factor core binding factor α-1 (Cbfa1) and bone-associated proteins.5 However, the similarities and differences between these processes have not yet been fully elucidated. Bone tissue is formed mainly through two different mechanisms. The first is ‘membranous bone formation’, exclusively seen in cranial flat bone development. In this mechanism, mesenchymal cells directly differentiate 1Division of Nephrology and Kidney Center, Kobe
University School of Medicine, Kobe, Japan; and 2Division of Intensive Care Medicine, Niigata
University Medical and Dental Hospital, Niigata, Japan Correspondence: M Fukagawa, Division of Nephrology and Kidney Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: [email protected] Kidney International (2007) 72
into osteoblasts. Most bones are formed through the second mechanism, ‘endochondral bone formation’, in which condensed mesenchymal cells initially differentiate into chondrocytes and produce cartilage matrix. The soft shell templates formed are subsequently replaced by osteoblasts and then ossified (Figure 1). These sequential processes of endochondral bone formation are regulated in detail by many crucial genes and proteins.6
Involvement of endochondral bone formation in intimal calcification has already been indicated by the presence of chondrocytes and osteoblasts within calcified atherosclerotic plaques. 7,8 Until recently, direct differentiation into osteoblasts was suspected to be the major mechanism in the development of medial calcification in CKD. 9 However, Neven and associates10 (this issue) now indicate the putative role of endochondral bone formation in medial calcification by demonstrating the presence of chondrocyte-like cells and the expression of specific markers for chondrocytes in the calcified tunica media in an animal model of CKD and in humans. These studies strongly support the involvement of endochondral bone formation in both medial and intimal calcification. Such findings certainly add new target points to be studied for establishing effective interventions for vascular calcification. So, what should be done to prove the functional involvement of this mechanism in vascular calcification? The first issue to be clarified is whether all processes involved in endochondral bone formation take place in vascular
Figure 1 | Time course and processes of endochondral bone formation. Initially formed cartilage tissue is absorbed by hematopoietic stem cell-derived macrophage-like cells, and replaced by bone tissue. (a) Cartilage tissue (dark blue) is formed with a poor blood supply. (b) Blood vessels penetrate into the cartilage tissue through the perichondrium. (c) Hematopoietic stem cell-derived macrophage-like cells absorb cartilage tissue and form a primitive bone marrow. (d) A magnified image of peri-bone marrow tissue. (1) Proliferation of chondrocytes. (2) Active production of cartilage matrix by mature chondrocytes. (3) Focal calcification around the atrophic chondrocytes. (4) Destruction of calcified tissue by hematopoietic stem cell-derived chondroclasts/ osteoclasts. (5) Invasion of osteoblasts from bone marrow space through the tunnel created by chondroclasts/osteoclasts, and production of bone matrix. 533
co mmentar y
calcification. As can be seen from the anatomy of the auricle, the presence of chondrocytes does not necessarily mean the development of endochondral bone formation. Furthermore, calcified and non-calcified portions are clearly separate in the bone. Thus, the time course needs to be demonstrated, and the initial mechanisms that trigger the transition from cartilage to bone tissue within the vessel wall need to be identified. If medial calcification also involves the processes of endochondral bone formation, another major issue remains to be clarified. What are the essential differences in the pathogenesis of calcification in the intima and in the media? Because medial calcification is often seen in the elderly and in patients with CKD or diabetes, a number of factors have been examined, such as uremic toxins, oxidative stress, and inflammation; however, they fail to explain the differences clearly. Future breakthroughs are certainly required to establish effective prevention and treatment modalities for medial calcification in CKD patients. REFERENCES 1.
Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–1483. 2. London GM, Guerin AP, Marchais SJ et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18: 1731–1740. 3. Moe SM, Chen NX. Pathophysiology of vascular calcification in chronic kidney disease. Circ Res 2004; 95: 560–567. 4. Kazama JJ, Amizuka N, Fukagawa M. Ectopic calcification as abnormal biomineralization. Ther Apher Dial 2006; 10 (Suppl 1): S34–S38. 5. Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 2004; 286: E686–E696. 6. Provot S, Schipani E. Molecular mechanisms of endochondral bone development. Biochem Biophys Res Commun 2005; 328: 658–665. 7. Fitzpatrick LA, Turner RT, Ritman ER. Endochondral bone formation in the heart: a possible mechanism of coronary calcification. Endocrinology 2003; 144: 2214–2219. 8. Bobryshev YV. Transdifferentiation of smooth muscle cells into chondrocytes in atherosclerotic arteries in situ: implications for diffuse intimal calcification. J Pathol 2005; 205: 641–650. 9. Moe SM, Duan D, Doehle BP et al. Uremia induces the osteoblasts differentiation factor Cbfa1 in human blood vessel. Kidney Int 2003; 63: 1003– 1011. 10. Neven E, Dauwe S, De Broe ME et al. Endochondral bone formation is involved in media calcification in rats and in men. Kidney Int 2007; 72: 574–581.
534
see original article on page 632
Can we do better than a single estimated GFR threshold when screening for chronic kidney disease? ED Poggio1 and AD Rule2 The Modification of Diet in Renal Disease (MDRD) equation has been used to screen for and diagnose chronic kidney disease (CKD). A fixed estimated glomerular filtration rate cutoff point has been advocated by the National Kidney Foundation to diagnose CKD. However, data derived from healthy individuals challenge this approach and suggest that age- and gender-specific reference values may be more useful in the screening setting. Kidney International (2007) 72, 534–536. doi:10.1038/sj.ki.5002452
The publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines by the National Kidney Foundation (NKF) in 2002 provided the medical community for the first time with a uniform definition of chronic kidney disease (CKD).1 These guidelines had the objective of timely management and treatment of this population at risk for increased mortality. This classification of CKD is based on three fundamental components: (1) an anatomical or structural component as evidenced by the presence of parenchymal renal disease (for example, abnormal imaging testing, abnormalities of the urine composition, and so on); (2) a temporal component in which the abnormalities are present for at least 3 months; and (3) a functional component based on glomerular filtration rate (GFR). Although all three are critical, the level of GFR is the pivot for staging the disease and determining the 1Department of Nephrology and Hypertension,
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA; and 2Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA Correspondence: ED Poggio, Renal Function Laboratory, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk A51, Cleveland, Ohio 44195, USA. E-mail: [email protected]
applicability of the recommended KDOQI treatment and management guidelines. Because direct GFR measurements are expensive and inconvenient, estimated GFR (eGFR) by the abbreviated Modification of Diet in Renal Disease (MDRD) equation has been the tool chosen by the NKF.1 An important consideration is that these guidelines define and classify CKD irrespective of cause of renal disease and make no distinction based on gender and age.2 For example, patients with stage 3 CKD (eGFR 30–59 ml/min/1.73 m2) are lumped together even though they represent a wide spectrum of ‘disease’ from a 35-year-old man with a progressive glomerulonephritis to a 65-year-old woman without risk factors for CKD but with a high-normal serum creatinine level. The MDRD equation was developed from nephrology referral patients identified by an elevated serum creatinine level (≥1.2 mg/dl in women and ≥1.4 mg/dl in men).3 To emphasize an early diagnosis of CKD, the NKF and the National Kidney Disease Education Program (NKDEP) generalized the use of the equation and recommend that all laboratories automatically report an eGFR with each serum creatinine test measured, irrespective of the clinical setting in which the test has been Kidney International (2007) 72
see original article on page 574
The making of a bone in blood vessels: From the soft shell to the hard bone M Fukagawa1 and JJ Kazama2 Vascular calcification, particularly of the medial layer of arteries, is one of the key determinants of survival in patients with chronic kidney disease. This abnormality is not merely a simple process of precipitation of calcium and phosphate but also includes several mechanisms similar to those of bone formation within the vessel wall. Kidney International (2007) 72, 533–534. doi:10.1038/sj.ki.5002440
Vascular calcification is a major abnormality of mineral and bone metabolism in chronic kidney disease (CKD)1 and is one of the major determinants of the risk of cardiovascular events and survival in patients with CKD. 2 In these patients, calcification develops not only in the intima, but also in the media of arteries, where it is known as Monckeberg’s medial sclerosis. 3 As for the pathogenesis, it has recently been well accepted that vascular calcification is not a simple process of precipitation of supersaturated calcium phosphate4 but also includes several mechanisms similar to those of bone formation in situ, such as expression of the osteoblast differentiation factor core binding factor α-1 (Cbfa1) and bone-associated proteins.5 However, the similarities and differences between these processes have not yet been fully elucidated. Bone tissue is formed mainly through two different mechanisms. The first is ‘membranous bone formation’, exclusively seen in cranial flat bone development. In this mechanism, mesenchymal cells directly differentiate 1Division of Nephrology and Kidney Center, Kobe
University School of Medicine, Kobe, Japan; and 2Division of Intensive Care Medicine, Niigata
University Medical and Dental Hospital, Niigata, Japan Correspondence: M Fukagawa, Division of Nephrology and Kidney Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: [email protected] Kidney International (2007) 72
into osteoblasts. Most bones are formed through the second mechanism, ‘endochondral bone formation’, in which condensed mesenchymal cells initially differentiate into chondrocytes and produce cartilage matrix. The soft shell templates formed are subsequently replaced by osteoblasts and then ossified (Figure 1). These sequential processes of endochondral bone formation are regulated in detail by many crucial genes and proteins.6
Involvement of endochondral bone formation in intimal calcification has already been indicated by the presence of chondrocytes and osteoblasts within calcified atherosclerotic plaques. 7,8 Until recently, direct differentiation into osteoblasts was suspected to be the major mechanism in the development of medial calcification in CKD. 9 However, Neven and associates10 (this issue) now indicate the putative role of endochondral bone formation in medial calcification by demonstrating the presence of chondrocyte-like cells and the expression of specific markers for chondrocytes in the calcified tunica media in an animal model of CKD and in humans. These studies strongly support the involvement of endochondral bone formation in both medial and intimal calcification. Such findings certainly add new target points to be studied for establishing effective interventions for vascular calcification. So, what should be done to prove the functional involvement of this mechanism in vascular calcification? The first issue to be clarified is whether all processes involved in endochondral bone formation take place in vascular
Figure 1 | Time course and processes of endochondral bone formation. Initially formed cartilage tissue is absorbed by hematopoietic stem cell-derived macrophage-like cells, and replaced by bone tissue. (a) Cartilage tissue (dark blue) is formed with a poor blood supply. (b) Blood vessels penetrate into the cartilage tissue through the perichondrium. (c) Hematopoietic stem cell-derived macrophage-like cells absorb cartilage tissue and form a primitive bone marrow. (d) A magnified image of peri-bone marrow tissue. (1) Proliferation of chondrocytes. (2) Active production of cartilage matrix by mature chondrocytes. (3) Focal calcification around the atrophic chondrocytes. (4) Destruction of calcified tissue by hematopoietic stem cell-derived chondroclasts/ osteoclasts. (5) Invasion of osteoblasts from bone marrow space through the tunnel created by chondroclasts/osteoclasts, and production of bone matrix. 533
co mmentar y
calcification. As can be seen from the anatomy of the auricle, the presence of chondrocytes does not necessarily mean the development of endochondral bone formation. Furthermore, calcified and non-calcified portions are clearly separate in the bone. Thus, the time course needs to be demonstrated, and the initial mechanisms that trigger the transition from cartilage to bone tissue within the vessel wall need to be identified. If medial calcification also involves the processes of endochondral bone formation, another major issue remains to be clarified. What are the essential differences in the pathogenesis of calcification in the intima and in the media? Because medial calcification is often seen in the elderly and in patients with CKD or diabetes, a number of factors have been examined, such as uremic toxins, oxidative stress, and inflammation; however, they fail to explain the differences clearly. Future breakthroughs are certainly required to establish effective prevention and treatment modalities for medial calcification in CKD patients. REFERENCES 1.
Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–1483. 2. London GM, Guerin AP, Marchais SJ et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18: 1731–1740. 3. Moe SM, Chen NX. Pathophysiology of vascular calcification in chronic kidney disease. Circ Res 2004; 95: 560–567. 4. Kazama JJ, Amizuka N, Fukagawa M. Ectopic calcification as abnormal biomineralization. Ther Apher Dial 2006; 10 (Suppl 1): S34–S38. 5. Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective. Am J Physiol Endocrinol Metab 2004; 286: E686–E696. 6. Provot S, Schipani E. Molecular mechanisms of endochondral bone development. Biochem Biophys Res Commun 2005; 328: 658–665. 7. Fitzpatrick LA, Turner RT, Ritman ER. Endochondral bone formation in the heart: a possible mechanism of coronary calcification. Endocrinology 2003; 144: 2214–2219. 8. Bobryshev YV. Transdifferentiation of smooth muscle cells into chondrocytes in atherosclerotic arteries in situ: implications for diffuse intimal calcification. J Pathol 2005; 205: 641–650. 9. Moe SM, Duan D, Doehle BP et al. Uremia induces the osteoblasts differentiation factor Cbfa1 in human blood vessel. Kidney Int 2003; 63: 1003– 1011. 10. Neven E, Dauwe S, De Broe ME et al. Endochondral bone formation is involved in media calcification in rats and in men. Kidney Int 2007; 72: 574–581.
534
see original article on page 632
Can we do better than a single estimated GFR threshold when screening for chronic kidney disease? ED Poggio1 and AD Rule2 The Modification of Diet in Renal Disease (MDRD) equation has been used to screen for and diagnose chronic kidney disease (CKD). A fixed estimated glomerular filtration rate cutoff point has been advocated by the National Kidney Foundation to diagnose CKD. However, data derived from healthy individuals challenge this approach and suggest that age- and gender-specific reference values may be more useful in the screening setting. Kidney International (2007) 72, 534–536. doi:10.1038/sj.ki.5002452
The publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines by the National Kidney Foundation (NKF) in 2002 provided the medical community for the first time with a uniform definition of chronic kidney disease (CKD).1 These guidelines had the objective of timely management and treatment of this population at risk for increased mortality. This classification of CKD is based on three fundamental components: (1) an anatomical or structural component as evidenced by the presence of parenchymal renal disease (for example, abnormal imaging testing, abnormalities of the urine composition, and so on); (2) a temporal component in which the abnormalities are present for at least 3 months; and (3) a functional component based on glomerular filtration rate (GFR). Although all three are critical, the level of GFR is the pivot for staging the disease and determining the 1Department of Nephrology and Hypertension,
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA; and 2Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA Correspondence: ED Poggio, Renal Function Laboratory, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk A51, Cleveland, Ohio 44195, USA. E-mail: [email protected]
applicability of the recommended KDOQI treatment and management guidelines. Because direct GFR measurements are expensive and inconvenient, estimated GFR (eGFR) by the abbreviated Modification of Diet in Renal Disease (MDRD) equation has been the tool chosen by the NKF.1 An important consideration is that these guidelines define and classify CKD irrespective of cause of renal disease and make no distinction based on gender and age.2 For example, patients with stage 3 CKD (eGFR 30–59 ml/min/1.73 m2) are lumped together even though they represent a wide spectrum of ‘disease’ from a 35-year-old man with a progressive glomerulonephritis to a 65-year-old woman without risk factors for CKD but with a high-normal serum creatinine level. The MDRD equation was developed from nephrology referral patients identified by an elevated serum creatinine level (≥1.2 mg/dl in women and ≥1.4 mg/dl in men).3 To emphasize an early diagnosis of CKD, the NKF and the National Kidney Disease Education Program (NKDEP) generalized the use of the equation and recommend that all laboratories automatically report an eGFR with each serum creatinine test measured, irrespective of the clinical setting in which the test has been Kidney International (2007) 72