<i>In silico</i> discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors

Choi, Jiwon,Lee, Kyungro,Kang, Myeongmo,Lim, Sung-Kil,Tai No, Kyoung Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.6

<P><B>Abstract</B></P> <P>The Wnt/β-catenin signaling pathway is a key regulator of bone homeostasis. Sclerostin act as an extracellular inhibitor of canonical Wnt signaling through high-affinity binding to the Wnt co-receptor LRP5/6. Disruption of the interaction between LRP5/6 and sclerostin has been recognized as a therapeutic target for osteoporosis. We identified a quinoxaline moiety as a new small-molecule inhibitor of the LRP5/6-sclerostin interaction through pharmacophore-based virtual screening, docking simulations, and <I>in vitro</I> assays. Structure-activity relationship studies and binding mode hypotheses were used to optimize the scaffold and yield the compound BMD4503-2, which recovered the downregulated activity of the Wnt/β-catenin signaling pathway by competitive binding to the LRP5/6-sclerostin complex. Overall, this study showed that the optimized structure-based drug design was a promising approach for the development of small-molecule inhibitors of the LRP5/6-sclerostin interaction. A novel scaffold offered considerable insights into the structural basis for binding to LRP5/6 and disruption of the sclerostin-mediated inhibition of Wnt signaling.</P> <P><B>Graphical abstract</B></P> <P>BMD4503-2 containing a quinoxaline moiety recovered the downregulated activity of the Wnt/β-catenin signaling pathway by competitive binidng to the LRP5/6-sclerostin complex.</P> <P>[DISPLAY OMISSION]</P>

코어운동과 밴드운동이 비만노인여성의 IL-6, TNF-α, VEGF 및 SCLEROSTIN에 미치는 영향

박인영(Park, In-Young) 한국체육과학회 2019 한국체육과학회지 Vol.28 No.4

The purpose of this study was to investigate the effects of core exercise and band exercise on IL-6, TNF-α, VEGF and SCLEROSTIN in obese elderly women. For this study, obese elderly women composed of core exercise and band exercise group(EX, n=10), the control group(CON, n=10). The variables of IL-6, TNF-α, VEGF and SCLEROSTIN were measured in all the subjects before the start and after the end of 12 week core exercise and band exercise program(40~60%HRR, 3 times per week, 60 mins). The test data were analyzed by paired t-test and 2-way ANOVA repeated measure, and the alpha level of p<.05 was set for all tests of significance. IL-6, TNF-α, VE GF a nd SCLE ROSTIN w ere measured p re a nd 12 weeks of post exercise training. IL-6(p<.05), TNF-α(p<.05), SCLEROSTIN(p<.01) was significantly decreased in EX group compared to CON group. VEGF(p<.05)were significantly increased in EX group compared to CON group. These results suggest that 12 weeks of core exercise and band exercis improves IL-6, TNF-α, VEGF and SCLEROSTIN. Thus, this core exercise and band exercis can be a useful therapy to improve IL-6, TNF-α, VEGF and SCLEROSTIN in obese elderly women.

Romosozumab for the treatment of osteoporosis

Michael R. McClung 대한골다공증학회 2018 Osteoporosis and Sarcopenia Vol.4 No.1

Romosozumab, a specific inhibitor of sclerostin, is a unique approach to therapy for postmenopausal osteoporosis and related disorders. The elucidation of sclerostin deficiency as the molecular defect of syndromes of high bone mass with normal quality, and the pivotal role of sclerostin as a mediator of osteoblastic activity and bone formation, provided the platform for the evaluation of inhibitors of sclerostin to activate bone formation. An extensive preclinical program and 2 large fracture endpoint trials with romosozumab, a sclerostin-binding antibody, have been completed. This review will highlight the results of those studies and describe the current status of romosozumab as a potential therapy for osteoporosis.

Conformational Dynamics of Sclerostin-LRP6 Complex Analyzed by HDX-MS

( Yejing Jeong ),( Jinuk Kim ),( Hee-jung Choi ),( Ka Young Chung ) 한국응용약물학회 2021 Biomolecules & Therapeutics(구 응용약물학회지) Vol.29 No.5

Sclerostin (SOST), a regulator of bone formation in osteocytes, inhibits the canonical Wnt signaling by interacting with low-density lipoprotein receptor-related protein 5/6 (LRP5/6) to prevent Wnt binding. Loss-of-function mutations of the SOST gene caused massive bone outgrowth and SOST-null mouse exhibited a high bone density phenotype. Therefore, SOST has been suggested as a promising therapeutic target for osteoporosis. A few previous studies with X-ray crystallography identified the binding interfaces between LRP6 and SOST, but there are limitations in these studies as they used truncated SOST protein or SOST peptide. Here, we analyzed the conformational dynamics of SOST-LRP6 E1E2 complex using hydrogen/deuterium exchange mass spectrometry (HDX-MS). We examined the effect of the C-terminal tail of SOST on LRP6 conformation upon complex formation. HDXMS analysis suggested a new potential binding interface for the C-terminal region of SOST that was missing from the previous crystal structure of the SOST-LRP6 E1E2 complex.

LRP5와 골량 획득의 새로운 지평

최제용 대한골대사학회 2012 대한골대사학회지 Vol.19 No.1

Lipoprotein receptor-related protein (LRP5) signaling is well correlated with the bone mass in both human and mice. Loss-of-function mutations of LRP5 result in osteopenia or osteoporosis. In contrast, gain-of-function mutations show high bone mass phenotype. To elucidate the molecular mechanism of the LRP5-mediated bone mass acquisition, several groups have genetically dissected the Wingless and Int-1 (Wnt) -catenin signaling pathway using osteoblast-lineage specific Cre mice. Key players for LRP5-mediated bone mass acquisition turn out to be different molecules with respect to the expressing tissue and action mode of these molecules. One is serotonin, a tryptophan metabolite that originates from duodenum, which acts as a negative regulator for bone formation. LRP5 suppresses serotonin biosynthesis by inhibiting the expression of tryptophan hydroxylase 1 in the gut. The other is sclerostin, an osteocyteproducing antagonist for LRP5 signaling. Here is a summary of recent findings about these two molecules, providing a chance to speculate new avenues in the LRP5-mediated bone mass acquisition. LRP5 신호는 사람이나 쥐에서 골량 획득과 잘 일치한다. LRP5의 기능-소실 돌연변이는 골감소나 골다공증을 초래하고기능-증가 돌연변이는 높은 골량을 나타낸다. LRP5로 인한 골량 조절 기전은 뼈모세포계 특이적으로 -catenin이나 LRP5를 제거하여 평가한 결과 두 유전자가 중요하게 관여한다고 알려졌다. 하나는 LRP5로 인한 골량은 골조직이 아닌 십이지장에서 발현되는 Serotonin이 호르몬처럼 작용하여 조절된다는 것이고, 다른 하나는 뼈세포에서 발현하는 Sclerostin이 뼈조직에서 국소적으로 작용하여 조절된다는 것이다. 여기서는 이 두 분자에 대한 최근 결과들을 요약하고 LRP5에 의한골량 획득의 새로운 기전에 대하여 알아보고자 한다.

New treatments of osteoporosis

Langdahl 대한골다공증학회 2015 Osteoporosis and Sarcopenia Vol.1 No.1

Osteoporosis is characterized by low bone mass, deteriorated bone architecture and increased risk of is fractures. The current available treatments of osteoporosis comprise antiresorptive and anabolic treatments. Bisphosphonates and RANKL antibody are the most widely used antiresorptive treatments while teriparatide is the only available anabolic treatment of osteoporosis. A common feature of antiresorptive as well as anabolic treatment is that bone resorption and formation remain coupled. Both types of treatment therefore establish a period of positive balance but because of the coupling, this period is temporary. The focus of this review is two new classes of anti-osteoporosis treatments; inhibition of cathepsin K and inhibition of sclerostin. Through very different mechanisms of action both may prove capable of uncoupling resorption and formation. Cathepsin K is a lysosomal cysteine protease that degrades bone matrix proteins including collagen type I. Animal and human studies have demonstrated that inhibition of cathepsin K leads to increased bone mass across species and reduced fracture risk in postmenopausal women. Sclerostin activates the Wnt canonical pathway and stimulates bone formation through stimulation of osteoblast differentiation, proliferation and survival. Short-term studies of antibody mediated inhibition of sclerostin in animals and postmenopausal women have consistently shown stimulation of bone formation and reduced or unaltered bone resorption. Clinical studies in postmenopausal women have shown increases in bone mass. If these two new treatments demonstrate anti-fracture efficacy at the same level or better as the best of the currently approved treatments, they will become valuable tools for improving the treatment of osteoporosis.

Lower uncarboxylated osteocalcin and higher sclerostin levels are significantly associated with coronary artery disease

Kim, Kyoung Min,Lim, Soo,Moon, Jae Hoon,Jin, Hyunjin,Jung, Kyong Yeun,Shin, Chan Soo,Park, Kyong Soo,Jang, Hak Chul,Choi, Sung Hee Elsevier 2016 Bone Vol.83 No.-

<P><B>Abstract</B></P> <P>Systemic roles for bone-derived proteins have emerged from recent studies. In particular, the serum concentration of osteocalcin (OCN) or sclerostin was found to be associated with altered glucose metabolism or atherosclerosis. The aims of this study were to evaluate OCN and sclerostin levels in subjects who underwent coronary artery bypass graft (CABG) surgery compared with those in normal controls and to analyze their relationships with atherosclerosis.</P> <P>This was an age- and sex-matched case–control study that included 61 male subjects who underwent CABG and 61 controls. Forty-six subjects (37.7%) with diabetes and 62 hypertensive subjects (50.8%) were included. Serum sclerostin, uncarboxylated OCN (ucOCN) and carboxylated OCN (cOCN) were measured. Coronary artery calcium (CAC) score was calculated according to Agatston's method, using a 64-slice multi-detector computed tomography scanner.</P> <P>The levels of serum ucOCN were significantly lower and sclerostin concentrations were higher in the CABG group than in the controls (<I>p</I> <0.05 for both), and these significances were maintained after adjusting for atherosclerotic risk factors in both diabetic and nondiabetic patients (<I>p</I> <0.05 in both groups). However, there was no difference in cOCN levels between CABG patients and controls. The group with abnormal CAC scores (CAC scores ≥100) had significantly higher levels of serum sclerostin (<I>p</I> <0.05). In multiple logistic regression analysis, both lower ucOCN and higher sclerostin levels were independently associated with CABG (odds ratio [OR] 0.43, 95% CI 0.22–0.84, <I>p</I> <0.05 for log(ucOCN); and OR 2.09, 95% CI 1.08–4.05, <I>p</I> <0.05 for log(sclerostin)).</P> <P>In subjects with CAD who underwent CABG, the serum ucOCN level was decreased and the sclerostin level was increased compared with those in the controls, regardless of diabetic status. Longitudinal studies are warranted to establish the precise roles of ucOCN and sclerostin in the pathogenesis of atherosclerosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Lower uncarboxylated osteocalcin and higher sclerostin concentrations are significantly associated with coronary artery disease regardless of diabetes status. </LI> <LI> Serum sclerostin level provided significant positive association with coronary artery calcification scores. </LI> <LI> In logistic regression analysis only uncarboxylated osteocalcin remained as an independent parameter for coronary artery disease requiring coronary artery bypass graft. </LI> </UL> </P>

Patients with non-ambulatory cerebral palsy have higher sclerostin levels and lower bone mineral density than patients with ambulatory cerebral palsy

Shin, Y.K.,Yoon, Y.K.,Chung, K.B.,Rhee, Y.,Cho, S.R. Pergamon Press 2017 Bone Vol.103 No.-

Bone loss is a serious clinical issue in patients with cerebral palsy (CP). Sclerostin has garnered interest as a key mechanosensor in osteocytes, leading to considerations of the therapeutic utilization of anti-sclerostin medications. This study was undertaken to determine associations among mechanical unloading, sclerostin levels, and bone imbalance in patients with CP. A total of 28 patients with CP participated in this cross-sectional study. The following measurements were taken: anthropometrics, clinical diagnosis of CP subtype and ambulatory status, bone mineral density (BMD) z-scores at the lumbar spine and hip, and blood biochemical markers, including sclerostin, parathyroid hormone (PTH), osteocalcin, C-terminal telopeptide, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, creatinine, calcium, and phosphorus. In analysis according to CP subtype, patients with spastic CP showed significantly lower BMD z-scores at the lumbar spine and femur neck regions than patients with dyskinetic CP. In analysis according to ambulatory status, patients with non-ambulatory CP showed significantly lower BMD z-scores at all lumbar spine and femoral sites, lower PTH and creatinine levels, and higher plasma sclerostin levels than patients with ambulatory CP. In regression analysis, ambulatory status was a significant determinant of plasma sclerostin levels. This study is the first to report on sclerostin levels and BMD in patients with CP, based on the hypothesis that patients who lack sufficient weight-bearing activities would show increased sclerostin levels and decreased BMD scores, compared with patients who sustain relatively sufficient physical activity. Therefore, this report may provide clinical insights for clinicians considering ambulatory status, sclerostin levels, and bone loss in patients with CP.

Decreased Serum Level of Sclerostin in Older Adults with Sarcopenia

안성희,정희원,이은주,백지연,장일영,박소정,이진영,최은아,이윤선,홍성빈,김범준 대한내분비학회 2022 Endocrinology and metabolism Vol.37 No.3

Background: Although muscles and bones interact with each other through various secretory factors, the role of sclerostin, an osteocyte-secreted factor, on muscle metabolism has not been well studied. We investigated the levels of serum sclerostin in Korean olderadults with sarcopenia. Methods: Blood samples were collected from 129 participants who underwent evaluation of muscle mass and function in an outpatient geriatric clinic of a teaching hospital. Sarcopenia and related parameters were determined using cutoff values for the Asian population. Serum sclerostin levels were measured using an enzyme-linked immunosorbent assay. Results: The mean age of the participants was 69.6 years, and 20 participants (15.5%) were classified as having sarcopenia. Afteradjusting for age, sex, and body mass index, serum sclerostin levels were significantly lower in participants with sarcopenia, lowmuscle mass, or weak muscle strength (P=0.003 to 0.045). Serum sclerostin levels were positively associated with skeletal muscleindex and grip strength after adjusting for confounders (P=0.001 and P=0.003), whereas sarcopenic phenotype score showed a negative association (P=0.006). These increases in muscle mass and strength were also dose dependent as serum sclerostin levels increased (P for trends=0.003 and P for trends=0.015). Higher serum sclerostin levels were associated with lower odds ratio (ORs)for sarcopenia, low muscle mass, and weak muscle strength after adjusting for confounders (OR, 0.27 to 0.50; P<0.001 to 0.025). Conclusion: Higher serum sclerostin levels were associated with a lower risk of sarcopenia, low muscle mass, and weak musclestrength in Korean older adults.

Increased Sclerostin Levels after Further Ablation of Remnant Estrogen by Aromatase Inhibitors

김원진,Yoon Jung Chung,Se Hwa Kim,Sehee Park1,Jae Hyun Bae,Gyuri Kim1,Su Jin Lee1,Jo Eun Kim1,박병우,임승길,이유미 대한내분비학회 2015 Endocrinology and metabolism Vol.30 No.1

Background: Sclerostin is a secreted Wnt inhibitor produced almost exclusively by osteocytes, which inhibits bone formation. Aromatase inhibitors (AIs), which reduce the conversion of steroids to estrogen, are used to treat endocrine-responsive breast cancer. As AIs lower estrogen levels, they increase bone turnover and lower bone mass. We analyzed changes in serum sclerostin levels in Korean women with breast cancer who were treated with an AI. Methods: We included postmenopausal women with endocrine-responsive breast cancer (n=90; mean age, 57.7 years) treated with an AI, and compared them to healthy premenopausal women (n=36; mean age, 28.0 years). The subjects were randomly assigned to take either 5 mg alendronate with 0.5 μg calcitriol (n=46), or placebo (n=44) for 6 months. Results: Postmenopausal women with breast cancer had significantly higher sclerostin levels compared to those in premenopausal women (27.8±13.6 pmol/L vs. 23.1±4.8 pmol/L, P<0.05). Baseline sclerostin levels positively correlated with either lumbar spine or total hip bone mineral density only in postmenopausal women (r=0.218 and r=0.233; P<0.05, respectively). Serum sclerostin levels increased by 39.9%±10.2% 6 months after AI use in postmenopausal women; however, no difference was observed between the alendronate and placebo groups (39.9%±10.2% vs. 55.9%±9.13%, P>0.05). Conclusion: Serum sclerostin levels increased with absolute deficiency of residual estrogens in postmenopausal women with endocrine-responsive breast cancer who underwent AI therapy with concurrent bone loss.