- The Changes in the Serum RANKL and OPG levels after Bone Marrow Transplantation: Association with Bone Mineral Metabolism.
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Hyun Jung Tae, Ki Hyun Baek, Eun Sook Oh, Ki Won Oh, Won Young Lee, Hye Soo Kim, Je Ho Han, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Choon Choo Kim, Moo Il Kang
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J Korean Endocr Soc. 2005;20(1):40-51. Published online February 1, 2005
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DOI: https://doi.org/10.3803/jkes.2005.20.1.40
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- BACKGROUND
The loss of bone mass is usually detected after bone marrow transplantation(BMT), particularly during the early post-transplant period. We recently reported that enhanced bone resorption following BMT was related to both the steroid dose and increase in IL-6. It was also suggested damage of the marrow microenvironment due to myeloablation and changes in bone growth factors contribute to post-BMT bone loss. Recently, the interactions of OPG and RANKL have been reported to be crucial in osteoclastogenesis and therefore in bone homeostasis. There are few data on the changes in RANKL/OPG status during the post-BMT period. This study investigated the changes in the levels of RANKL and OPG during the post-BMT period, and also assessed whether the changes in these cytokine levels actually influenced bone turnover and post-BMT bone loss. METHODS: We prospectively investigated 110 patients undergoing allogenic BMT and analyzed 36 (32.4+/-1.3 years, 17 men and 19 women) where DEXA was performed before and 1 year after the BMT. The serum bone turnover marker levels were measured before and 1, 2, 3, 4 and 12 wks, 6 Ms, and 1 yr after the BMT. The serum sRANKL and OPG levels were measured in all patients before and 1, 3 and 12 wks after the BMT. RESULTS: The mean bone losses in the lumbar spine and total proximal femur, which were calculated as the percent change from the baseline to 1 yr, were 5.2(P<0.01) and 11.6%(P<0.01), respectively. The mean serum ICTP, a bone resorption marker, increased progressively until 3 and 6 months after the BMT, but decreased gradually thereafter, reaching the basal values after 1 year. The serum osteocalcin levels decreased progressively until 3 wks after the BMT, then increased transiently at 3 and 6 Ms, but returned to the basal level by 1 yr. The serum sRANKL and OPG levels had increased significantly by weeks 1 and 3 compared with the baseline(P<0.01), but decreased at 3 months. The sRANKL/OPG ratio increased progressively until 3 weeks, but then decreased to the basal values. During the observation period, the percent changes from the baseline in the serum RANKL levels and RANKL/OPG ratio showed positive correlations with the percent changes from the baseline serum ICTP levels. Patients with higher RANKL levels and RANKL/OPG ratio during the early post-BMT period lost more bone mass at the lumbar spine. CONCLUSION: In conclusion, dynamic changes in the sRANKL and OPG levels were observed during the immediate post-BMT period, which were related to a decrease in bone formation and loss of L-spine BMD during the year following the BMT. Taken together, these results suggest that increased sRANKL levels and sRANKL/OPG ratios could be involved in a negative balance in bone metabolism following BMT.
- The Effects of Aging on the Proliferation and Differentiation of Osteoblasts from Human Mesenchymal Stem Cells.
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Ki Hyun Baek, Hyun Jung Tae, Ki Won Oh, Won Young Lee, Chung Kee Cho, Soon Yong Kwon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Choon Choo Kim
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J Korean Endocr Soc. 2003;18(3):296-305. Published online June 1, 2003
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Abstract
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- BACKGROUND
Osteoblasts originate from osteoprogenitor cells in bone marrow stroma, termed mesenchymal stem cells (MSCs) or bone marrow stromal cells. Each MSC forms colonies (colony forming units-fibroblasts [CFU-Fs]) when cultured ex vivo. There are some reports about the age-related changes of the number and osteogenic potential of osteoprogenitor cells, but any relationship has not been clearly established in humans. In this study, we counted MSCs using CFU-Fs count and examined the proliferative capacity and differentiation potential of osteoprogenitor cells. Finally, we analyzed how these parameters varied with donor age. METHODS: Bone marrow was obtained from the iliac crest of young (n=6, 27.2+/-8.6 years old) and old (n=10, 57.4+/-6.7 years old) healthy donors. Mononuclear cells, including MSCs, were isolated and cultured in osteogenic medium. In primary culture, we compared the colony-forming efficiency of MSCs between the two groups and determined the matrix calcification. When primary culture showed near confluence, the cells were subcultured. Alkaline phosphatase activity, osteocalcinexpression by RT-PCR and proliferative potential by MTT assay were examined by the time course of secondary culture. RESULTS: At the 15th day of primary culture, the mean number of CFU-Fs was significantly higher in the younger donors (young: 148.3+/-28.9, old: 54.3+/-9.1, p=0.02) and the mean size of CFU-Fs was also larger in the younger donors than the older donors. However, matrix calcification was not different between the two groups (young: 103.6+/-50.6, old: 114.0+/-56.5, p=NS). In secondary culture, alkaline phosphatase activities were significantly lower in the older donors. The younger donors showed peak alkaline phosphatase activity at day 10, while the older donors didn't showed a remarkable peak (young: 935.5+/-115.0U/mg, old: 578.4+/-115.7U/mg, p<0.05). Total cell number as a proliferative index increased progressively during the secondary culture and a significantly greater cell number was noted in the younger donors. Osteocalcin expression was generally upregulated in the younger donors, but this was not statistically significant. CONCLUSION: Our study shows that the number of osteoprogenitor cells is decreased during aging and that the proliferative capacity and differentiation potential of osteoprogenitor cells seem to be reduced during aging.
- The Changes of Serum Growth Factors after Hematopoietic Stem Cell Transplantation: Impact on Bone Mineral Metabolism.
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Ki Hyun Baek, Eun Sook Oh, Ki Won Oh, Won Young Lee, Hye Soo Kim, Soon Yong Kwon, Je Ho Han, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Choon Choo Kim
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J Korean Endocr Soc. 2002;17(5):664-674. Published online October 1, 2002
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Abstract
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- BACKGROUND
A loss of bone mass is usually detected after a bone marrow transplantation (BMT), especially during the early post-transplant period. We recently reported that enhanced bone resorption following a BMT was related to both the steroid dose and the increase in IL-6. We also suggested damage to the marrow stromal microenvironment, by myoablation, partly explains the impaired bone formation following a BMT. It is well known that some growth factors play important role in bone growth and osteogenesis. However, the pathogenetic role of bone growth factors in post-BMT bone loss is unknown and data on the changes in the growth factors, in accordance with bone turnover markers and bone mineral density (BMD) changes are scarce. We investigated changes in bone growth factors such as IGF-I (Insulin-like growth factor-I), fibroblast growth factor-2 (FGF-2) and Macrophage colony stimulating factor (M-CSF), during the post-BMT period, and assessed whether the growth factor changes influenced the bone turnover and post-BMT bone loss. The present study is the first prospective study to describe the changes in bone growth factors following a BMT. METHODS: We prospectively investigated 110 patients undergoing a BMT, and analyzed 36 patients (32.4+/-1.3 years, 17 men and 19 women) whose BMDs were measured before, and 1 year after, the BMT. The serum biochemical markers of bone turnover were measured before, 1, 2, 3 and 4 weeks, 3 and 6 months, and 1 year, after the BMT. The serum FGF-2, IGF-I and M-CSF levels were measured before and 1 and 3 weeks, and 3 months after the BMT. The correlation between the changes of growth factors and various bone parameters was analyzed. RESULTS: The mean bone losses in the lumbar spine and total proximal femur, calculated as the percentage change from the baseline to the level at 1 year, were 5.2 (p<0.05) and 11.6% (p<0.01), respectively. The serum type I carboxyterminal telopeptide (ICTP), a bone resorption marker, increased progressively until 6 months after the BMT, but thereafter decreased, to the base value after 1 year. Serum osteocalcin, a bone formation marker, decreased progressively, until 3 weeks after the BMT but then increased transiently, and finally returned to the base level at 1 year. The serum IGF-I and FGF-2 also decreased progressively until 3 weeks and 1 week after the BMT, respectively, then increased to the base values at 3 months. The serum M-CSF increased briskly at 1 week post-BMT, then decreased to the base level. There were positive correlations between the percentage changes from the baseline proximal femur BMD and the IGF-I levels 3 weeks and 3 months (r=0.52, p<0.01, r=0.41, p<0.05) post BMT. A Significant correlation was found between the IGF-I and osteocalcin levels pre-BMT, and 3 weeks after the BMT. Another positive correlation was found between the M-CSF and the ICTP levels at 3 weeks post BMT (r=0.54, p<0.05). CONCLUSION: In conclusion, there were significant changes in the serum IGF-I, FGF-2 and M-CSF levels in the immediate post-BMT period, which were related to a decrease in bone formation and loss in the proximal femoral BMD during the year following the BMT
- The Effect of Hematopoietic Stem Cell Transplantation in the Origin and the Osteoblastic Differentiation of the Human Bone Marrow Stromal Cell.
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Moo Il Kang, Seong Won Cho, Eun Sook Oh, Ki Hyun Baik, Won Young Lee, Ki Won Oh, Hye Soo Kim, Je Ho Han, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Choon Choo Kim
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J Korean Endocr Soc. 2000;15(4-5):571-581. Published online January 1, 2001
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Abstract
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- BACKGROUND
Bone marrow transplantation is the treatment of choice for patients with certain- hematological malignancies, many of whom will survive many years thereafter. Bone disease is a potential longterm complication. But, little is known about the effects of bone marrow transplantation on bone. METHODS: In this study, bone marrow was obtained from healthy donor and transplant recipients. Then mononuclear cells including marrow stromal cells were isolated and cultured. At near confluence, bone marrow stromal cells were subcultured. Thereafter alkaline phosphatase activities of each group were measured by time course of secondary culture. We also analysed the origin of marrow stromal cells by the polymerase chain reaction using YNZ 22 minisatellite probe. RESULTS: l. Cells cultured in our system showed the characteristics of marrow stromal cells differentiated to osteoblasts. They were in fibroblast-like spindle shape and positive to alkaline pbosphatase histochemistry and Von Kossa histochemistry in secondary cultures. 2. The time required for the near confluence in the primary culture was 15 days and 22.9 days on the average in healthy donors and transplant recipients, respectively (p=0.003). 3. In secondary cultures, healthy donors and transplant recipients showed peak alkaline phosphatase activity at 10 days and 17 days, respectively (p=0.031). Alkaline phosphatase activity was lower in BMT recipients than in healthy donors during the whole period of secondary cultures. 4. In polymerase chain reaction analysis using YNZ 22 minisatellite probe, bone marrow stromal cells were of recipient origin. CONCLUSION: Recipient-derived bone marrow stromal cells may be damaged secondary to the effect of chemotherapy, glucocorticoid & total body irradiation which have given before bone marrow transplantation. So it may affect the differentiation of bone marrow stromal cells into the osteoblasts.
- The Effect of Bone Marrow Transplantation on Bone Mineral Metabolism: 2 - Year Prospective Study.
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Won Young Lee, Moo Il Kang, Eun Sook Oh, Ki Won Oh, Je Ho Han, Hyun Shik Son, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Wan Sik Shin, Woo Sung Min, Choon Choo Kim
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J Korean Endocr Soc. 2000;15(4-5):561-570. Published online January 1, 2001
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- BACKGROUND
Loss of bone mass is usually detected after bone marrow transplantation (BMT), especially during the early post-transplant period. But little is known about the long-term effects of BMT on bone mineral metabolism. METHODS: We have investigated prospectively 12 patients undergoing BMT (4 autologous, 8 allogeneic) for hematologic diseases (8 leukemia, 3 SAA, 1 MDS). Serum concentrations of calcium, phosphorus, creatinine, gonadotropins, sex hormones and bone turnover markers (osteocalcin and ICTP) were measured. The samples were collected before BMT and 1, 2, 3, 4, and 12 weeks, 6 months and 1, 2 years thereafter. Bone mineral density (BMD) was measured with DEXA (Dual Energy X-ray Absorptiometry) before BMT, 1 year and 2 year after BMT. In patients with amenorrbea, hormone replacement therapy was started from around 1 year after BMT RESULTS: 1. The mean bone loss in the lumbar spine, calculated as the percent change from the baseline to the level at 1 year and 2 year was 7.3% and 1.9%, respectively. The mean bone loss in the total proximal femur from the baseline to the level at 1 year and 2 year was 8.0% and 8.3% respectively. 2. The serum ICTP increased progressively until four weeks after BMT. Thereafter, it decreased gradually to reach basal values after one year and thereafter no more change until 2 year. Serum osteocalcin decreased progressively until three weeks after BMT. After that, it increased and reached basal values after 3 months. Osteocalcin increased at 6 month transiently but thereafter, it decreased to the level of slightly above basal value at 2 year. 3. Patients who were treated with TBI or pateints with GVHD had a tendency of lower BMD at l year and 2 year after BMT than those of patients without TBI or GVHD. 4. Eight out of nine women went into a menopausal state immediately after BMT and remained amenorrhea, evidenced by high gonadotropins and low estradiol levels. In contrast to women, gonadotropins and testosterone levels were not changed significantly in men after BMT. CONCLUSION: The rapid impairment of bone formation and the increase in bone resorption, as shown by the biochemical markers in this study, might play a role in bone loss after BMT. The efficacy of HRT for the correction of hypogonadism and bone loss was evidenced by 2 year BMD which was much more increased compared to 1 year BMD, especially in vertebra.
- The Nonthyroidal Illness Syndrome: Prognostic Value and Circulating Cytokines after Allogeneic Bone Marrow Transplantation.
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Ki Won Oh, Moo Il Kang, Won Young Lee, Hyun Shik Son, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Wan Sik Shin, Woo Sung Min, Choon Choo Kim, Byung Young Ahn, Hyung Sun Sohn
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J Korean Endocr Soc. 2000;15(2):214-225. Published online January 1, 2001
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- BACKGROUND
Alteration of thyroid hormone parameters are frequently observed in sick patients and commonly known as nonthyroidal illness syndrome(NTIS) or euthyroid sick syndrome(ESS). NTIS is seen in starvation, surgery, severe illness, and also bone marrow transplantation(BMT). The degree of reduction in thyroid hormone parameters correlated with the severity of NTIS and might predict the prognosis of underlying illness. Recently, particular attention is focused on the role of cytokines in developing the NTIS. This prospective study was designed to assess the relationship of serum thyroid hormone parameters and serum cytokine levels before and in the short-term follow-up after allogeneic BMT in order to predict patients outcome. METHODS: Included 80 patients that were mainly leukemia and severe aplastic anemia. Serum thyroid hormone parameters and serum cytokine levels were measured before and 7, 14, 21, 28 days and 3, and 6 months after BMT. RESULTS: Near-all patients experienced significant decrease of thyroid hormone levels and also significant increase of cytokine levels after BMT. After post-BMT 3 weeks, the serum cytokine levels were negatively correlated with the serum T3 and T4 levels, but not with the serum TSH levels. The patients treated with high-dose steroid or total-body irradiation tended to show lower levels of TSH and more delayed recovery compared to non-treated patients. The patients died after BMT represented generally lower levels of all thyroid hormone parameters than survival patients during entire follow-up period. CONCLUSION: Development of NTIS is associated with higher probability of fatal outcome after BMT and has prognostic relationship in this group of patients. Increased levels of cytokines, especially IL-6 and TNF-alpha, are often found in post-BMT NTIS patients and correlated with the changes in the levels of thyroid hormone parameters.
- The Changes of Cytokines and Bone Turnover Markers after Bone Marrow Transplantation.
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Won Young Lee, Moo Il Kang, Ki Won Oh, Hye Soo Kim, Seong Dae Mun, Je Ho Han, Hyun Shik Son, Sung Koo Kang, Wan Sik Shin, Woo Sung Min, Choon Choo Kim
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J Korean Endocr Soc. 2000;15(1):85-96. Published online January 1, 2001
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Loss of bone mass is usually detected after BMT. The causes of bone loss are related with gonadal dysfunction and immunosuppressants. Cytokines, especially IL-6, play an important role in the pathogenesis of postmenopausal osteoporosis. However, the pathogenetic role of cytokines in post-BMT bone loss is unknown and data on the changes of cytokines in accordance with bone turnover markers are scarce. The aim of this study is to assess the relationship of bone turnover markers and cytokines of peripheral blood and bone marrow before and after allogeneic BMT. METHODS: This prospective study included two analyses. The first was a study of 46 BMT recipients, examining the relationship between bone turnover markers and cytokines of serum which were measured before and 1, 2, 3, 4 week and 3 months after BMT. The second was a study of 14 BMT patients, measuring bone marrow plasma cytokines such as IL-6 and TNF-alpha at post-BMT 3 week and bone turnover marker at the same time to assess the relationship between two parameters. RESULTS: Serum ICTP, bone resorption marker, increased progressively until 4 weeks (peak) after BMT and then decreased thereafter. Serum osteocalcin, bone formation marker, decreased progressively until 3 weeks after BMT and then increased thereafter. There was positive correlation between serum ICTP and bone marrow IL-6 levels at the post-BMT 3 week with a statistical significance, but the correlation between bone turnover markers and bone marrow TNF-alpha or peripheral blood cytokines was not found. CONCLUSION: Our data suggest that the progressive increase of bone resorption after BMT is related with the increase of bone marrow IL-6, which is a potent stimulator of bone resorption in vivo.
- Analysis of HLA-DQA1 genotype in Korea autoimmune thyroid disease and IDDM patients.
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Moo Il Kang, Je Ho Han, Soon Jip Yoo, Jong Min Lee, Hyun Sik Son, Kun He Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Ku Kang, Choon Choo Kim, Dong Jip Kim
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J Korean Endocr Soc. 1992;7(4):320-330. Published online January 1, 2001
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- No abstract available.
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