Renal Handling of Sclerostin in Response to Acute Glomerular Filtration Decline.

Deterioration of glomerular filtration rate (GFR) is associated with alterations of bone metabolism. It translates clinically to bone fragility and increased fractures rate among patients with impaired GFR. Recently, sclerostin (SCL) gained much attention as an important factor in pathogenesis of mineral and bone disturbances in patients with renal diseases. There is no data about SCL behaviour in patients with acute GFR decline. The aim of this study was to evaluate the renal handling of SCL. This is a prospective, single-centre observational study in patients undergoing nephrectomy due to urological indications. Serum and urinary SCL levels were measured prior and after nephrectomy. 25 patients were enrolled. After surgery, eGFR significantly declined (from 87.4±19.7 to 67.7±25.7 ml/min/1.73 m(2), p<0.0001). Nephrectomy caused more than 20 times higher renal fractional excretion of SCL [0.15 (interquartile range, IQR 0.09-0.40) vs. 2.78 (IQR 1.51-4.02)%, p<0.001], while its serum level remained intact [0.69 (IQR 0.57-0.90 vs. 0.65 (IQR 0.53-0.88) ng/ml, p=0.4]. The magnitude of eGFR reduction was associated inversely with change in urinary SCL fractional excretion (r=-0.6, p=0.001) and with alteration in serum SCL level (r=-0.5, p=0.01). Our results suggest that increased serum SCL concentrations at moderately reduced GFR are not due to diminished renal clearance. At more severely decreased GFR, elevated SCL concentration results from both increased production and reduced renal elimination.

Renal elimination of sclerostin increases with declining kidney function.

CONTEXT: Sclerostin serum levels are increased in patients with chronic kidney disease (CKD). Osteoporosis and CKD often occur simultaneously. Currently antisclerostin antibodies are in clinical development for the treatment of osteoporosis. OBJECTIVE: The objective of this study was to study the renal handling of sclerostin. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a university hospital and outpatient renal clinic. PATIENTS: One hundred twenty men and women with CKD stage 1-5 participated in the study. INTERVENTION: Measurements of sclerostin in urine and serum (ELISA), renal function [estimated glomerular filtration rate (eGFR)], electrolytes, α1-microglobulin, PTH, vitamin D, and markers of bone turnover were conducted. Eight human kidney biopsies were stained for sclerostin using immunohistochemistry. MAIN OUTCOME MEASURE: Urinary excretion of sclerostin was measured. RESULTS: Urinary sclerostin excretion increased with declining eGFR (R=-0.75, P<.001), from 10.4 (±12.7) pmol/L in patients with eGFR greater than 90 mL/min per 1.73 m2 (CKD stage 1) to 117.9 (±65.4) pmol/L in patients with eGFR less than 15 mL/min per 1.73 m2 (CKD stage 5, P<.001). Fractional excretion of sclerostin increased with declining eGFR (R=-0.83, P<.001) from 0.45% (±0.6%) in CKD 1 to 26.3% (±17.6%) in CKD 5 (P<.001). Fractional excretion of sclerostin correlated with fractional excretion of α1-microglobulin (R=0.82, P<.001). No association between serum sclerostin and fractional excretion of phosphorus was found in a multivariate analysis. Sclerostin was detected in proximal tubular cells, showing a diffuse cytoplasmic staining pattern. CONCLUSION: Increased sclerostin serum levels in CKD patients are not due to decreased renal elimination. On the contrary, renal elimination increases with declining kidney function. Whether this has consequences on antisclerostin antibody dosing, efficacy, or safety in patients with CKD remains to be determined.

[Treatment of long bone fracture nonunion in limbs by bone morphogenetic protein compounds combined with autologous red bone marrow graft].

OBJECTIVE: To observe the clinical therapeutic effect of treatment for long bone fracture nonunion in limbs by bone morphogenetic protein compounds combined with autologous red bone marrow graft. METHODS: From January 2004 to December 2010,36 cases of long bone fracture nonunion in limbs were treated by bone morphogenetic protein compounds combined with autologous red bone marrow graft. There were 22 males and 14 females with an average age of 36.8 years old ranging from 22 to 68 years. Nonunion sites included humerus in 6 cases,ulna in 4 cases,radius in 3 cases,femur in 10 cases,and tibia in 13 cases. The latest reconstruction was performed on these 36 cases during 8 to 24 months (means 13.7 months) after injuries. There were 22 cases of hypertrophic nonunion,14 cases of atrophic nonunion. Main clinical symptoms were pain of fracture sites on weight bearing: and swelling of limbs. Clearness of fracture line and bone defect were indicated on X-ray. The therapeutic effect of the treatment after operation was been evaluated by wound healing, reaction in the area of bone graft and bone marrow aspiration,fracture healing,and recovery of adjacent joint function. RESULTS: All incisions primarily healed,immunologic rejection and anaphylaxis were not detected in these incisions. Infection and haematoma formation were not detected in the area of bone marrow aspiration. All these 36 cases were followed up for 3 to 20 months (means 16.2 months). Chronic pain in the area of bone marrow aspiration, bone infection in the area of bone graft, and red swelling of the skin near incisions or sinus tract were not detected. Bony union was achieved in all cases in 3 to 12 months (means 6.2 months) after operation, malunion was not detected. Pain of fracture sites on weight bearing and swelling of limbs disappeared after bony union. The adjacent joint function completely recovered in most cases,only 5 cases remained some function limited part. CONCLUSION: In the treatment of long bone fracture nonunion in limbs, bone morphogenetic protein compounds combined with autologous red bone marrow graft have the advantage of wide range of sources, safety and promoting bone union,which is one of the ideal bone graft

Paediatric reference values for the C-terminal fragment of fibroblast-growth factor-23, sclerostin, bone-specific alkaline phosphatase and isoform 5b of tartrate-resistant acid phosphatase.

BACKGROUND: Paediatric reference values for novel markers of phosphate homeostasis, bone formation and resorption and their putative relationship to growth are lacking. METHODS: A total of 424 healthy children, adolescents and young adults (221 males) aged 0.1-21 y, were enrolled in this cross-sectional study. Height, weight and height velocity were assessed. Plasma/serum samples for determination of C-terminal fragment of fibroblast growth factor-23 (cFGF-23), sclerostin, bone alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase 5b (TRAP5b) were available from 222, 264, 352 and 338 individuals, respectively. Calculation of cross-sectional centiles and z-scores was based on median (M), standard coefficient of variation (S) and the Box-Cox power (L) of transformation (LMS method) per age cohort. Correlations between variables as well as with growth were assessed. RESULTS: cFGF-23, BAP and TRAP5b were significantly correlated with age (each P < 0.01), with highest values during infancy and adolescence. Serum levels of BAP and TRAP5b were significantly higher in adolescent boys compared with girls (each P < 0.01). In contrast, sclerostin levels were independent of age and gender. BAP and TRAP5b were strongly correlated and both were significantly associated with cFGF-23 and sclerostin as well (each P < 0.01). cFGF-23 was positively correlated with serum phosphate and renal phosphate threshold concentration (each P < 0.01). Height, weight, body mass index and height velocity were weakly correlated with BAP and TRAP5b (each P < 0.05). CONCLUSIONS: This study provides age- and gender-related centile charts and z-scores for cFGF-23, BAP, TRAP5b and sclerostin and highlights the link between phosphate homeostasis and markers of bone metabolism during growth.

Biomarkers in spondyloarthritis.

Key challenges in the management of spondyloarthritis focus on the lack of availability of measures of disease activity and the inability to predict joint damage or response to treatment, which is expensive and associated with potentially serious toxicity. Recent studies have focused on the possible contribution of soluble biomarkers, which have been selected based on current understanding of their role in inflammation and/or their association with turnover of joint matrix. Emerging candidates for disease activity markers include interleukin-6 and soluble cytotoxic T lymphocyte associated molecule-4. Potential predictors of damage include metalloproteinase-3 and sclerostin. Acute-phase reactants C-reactive protein and serum amyloid A and interleukin-6 are currently the best predictors of treatment response. Significant study limitations are small sample size and the lack of multivariate analyses that can determine whether the biomarker contributes information that is independent of other clinical and laboratory variables used in routine care.

Urine release of systemically administered bone morphogenetic protein hybrid molecule.

BACKGROUND: Although it is well known that TGF-beta circulates, the presence and activity of endogenous bone morphogenetic proteins (BMPs) in biological fluids has not been studied. Here we investigated the urine secretion of a systemically administered BMP hybrid molecule. METHODS: A dimeric recombinant human BMP molecule consisting of the BMP-7 prodomain and the BMP-6 mature domain was constructed and injected into Sprague Dawley rats. The blood was collected from the rats' orbital plexus, and 24-hour urine samples were pooled and purified using a heparin sepharose column. Protein identity was confirmed by Western blot and by liquid chromatography-mass spectrometry (LC-MS) of the resulting peptides. Urine-derived protein from the 35-kDa band was bound to inactive demineralized bone matrix and implanted subcutaneously into rats. RESULTS: Western blot analysis of sera demonstrated that BMP-7/6 remained intact in the rat plasma and could still be visualized 30 minutes after its systemic administration. Two protein bands at 35 and 39 kDa were detected with anti-BMP antibodies in the urine of rats, corresponding to the mature active BMP-6 dimer and the prodomain of BMP-7, respectively. LC-MS analysis detected only peptides derived from the BMP-7/6 molecule. Histological analysis of implanted pellets revealed formation of a new endochondral bone 14 days following implantation. CONCLUSIONS: These results show for the first time that systemically administered BMP-7/6 hybrid molecule is secreted into the urine and that its biological activity is preserved, suggesting that analysis of BMP in urine might reflect its presence in serum.