Lack of CD47 impairs bone cell differentiation and results in an osteopenic phenotype in vivo due to impaired signal regulatory protein α (SIRPα) signaling.

Here, we investigated whether the cell surface glycoprotein CD47 was required for normal formation of osteoblasts and osteoclasts and to maintain normal bone formation activity in vitro and in vivo. In parathyroid hormone or 1α,25(OH)2-vitamin D3 (D3)-stimulated bone marrow cultures (BMC) from CD47(-/-) mice, we found a strongly reduced formation of multinuclear tartrate-resistant acid phosphatase (TRAP)(+) osteoclasts, associated with reduced expression of osteoclastogenic genes (nfatc1, Oscar, Trap/Acp, ctr, catK, and dc-stamp). The production of M-CSF and RANKL (receptor activator of nuclear factor κß ligand) was reduced in CD47(-/-) BMC, as compared with CD47(+/+) BMC. The stromal cell phenotype in CD47(-/-) BMC involved a blunted expression of the osteoblast-associated genes osterix, Alp/Akp1, and α-1-collagen, and reduced mineral deposition, as compared with that in CD47(+/+) BMC. CD47 is a ligand for SIRPα (signal regulatory protein α), which showed strongly reduced tyrosine phosphorylation in CD47(-/-) bone marrow stromal cells. In addition, stromal cells lacking the signaling SIRPα cytoplasmic domain also had a defect in osteogenic differentiation, and both CD47(-/-) and non-signaling SIRPα mutant stromal cells showed a markedly reduced ability to support osteoclastogenesis in wild-type bone marrow macrophages, demonstrating that CD47-induced SIRPα signaling is critical for stromal cell support of osteoclast formation. In vivo, femoral bones of 18- or 28-week-old CD47(-/-) mice showed significantly reduced osteoclast and osteoblast numbers and exhibited an osteopenic bone phenotype. In conclusion, lack of CD47 strongly impairs SIRPα-dependent osteoblast differentiation, deteriorate bone formation, and cause reduced formation of osteoclasts.

Effects of carprofen on renal function during medetomidine-propofol-isoflurane anesthesia in dogs.

OBJECTIVE: To investigate effects of carprofen on indices of renal function and results of serum bio-chemical analyses and effects on cardiovascular variables during medetomidine-propofol-isoflurane anesthesia in dogs. ANIMALS: 8 healthy male Beagles. PROCEDURES: A randomized crossover study was conducted with treatments including saline (0.9% NaCl) solution (0.08 mL/kg) and carprofen (4 mg/kg) administered IV. Saline solution or carprofen was administered 30 minutes before induction of anesthesia and immediately before administration of medetomidine (20 microg/kg, IM). Anesthesia was induced with propofol and maintained with inspired isoflurane in oxygen. Blood gas concentrations and ventilation were measured. Cardiovascular variables were continuously monitored via pulse contour cardiac output (CO) measurement. Renal function was assessed via glomerular filtration rate (GFR), renal blood flow (RBF), scintigraphy, serum biochemical analyses, urinalysis, and continuous CO measurements. Hematologic analysis was performed. RESULTS: Values did not differ significantly between the carprofen and saline solution groups. For both treatments, sedation and anesthesia caused changes in results of serum biochemical and hematologic analyses; a transient, significant increase in urine alkaline phosphatase activity; and blood flow diversion to the kidneys. The GFR increased significantly in both groups despite decreased CO, mean arterial pressure, and absolute RBF variables during anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen administered IV before anesthesia did not cause detectable, significant adverse effects on renal function during medetomidine-propofol-isoflurane anesthesia in healthy Beagles.

Effects of acepromazine on renal function in anesthetized dogs.

OBJECTIVE: To investigate the effects of IM administration of acepromazine on indices of relative renal blood flow and glomerular filtration rate (GFR) by means of scintigraphy, as well as the effects on physiologic, hematologic, and serum biochemical variables in anesthetized dogs, compared with effects of administration of saline. ANIMAL: 6 healthy Beagles. PROCEDURE: Acepromazine (0.1 mg/kg) or physiologic saline (0.9 NaCI) solution was administered IM 30 minutes prior to induction of anesthesia with thiopentone; anesthesia was maintained with inspired isoflurane for 2.25 hours. Blood gases and circulatory and ventilatory variables were monitored. Renal function was evaluated by scintigraphic measurements of GFR and relative renal blood flow and analyses of serum and urine. Statistical analyses used ANOVA or Friedman ANOVA. RESULTS: Values of relative renal blood flow and GFR remained high despite low blood pressures. After administration of acepromazine, mean +/- SD arterial blood pressure was 66 +/- 8 mm Hg during anesthesia; this value was below the threshold (80 mm Hg) for renal autoregulation of GFR. In comparison, mean arterial blood pressure after administration of saline was significantly higher (87 +/- 13 mm Hg). However, between treatments, there were no significant differences in GFR, relative renal blood flow, or other indices of renal function. CONCLUSIONS AND CLINICAL RELEVANCE: Measurements of renal function and blood flow in dogs during anesthesia with thiopentone and isoflurane did not differ significantly between treatments, which suggested that acepromazine protects renal function despite inducing reduction in blood pressure, compared with effects of administration of saline.

Effects of carprofen on renal function and results of serum biochemical and hematologic analyses in anesthetized dogs that had low blood pressure during anesthesia.

OBJECTIVE: To investigate effects of IV administered carprofen on indices of renal function and results of serum biochemical and hematologic analyses in dogs anesthetized with acepromazine-thiopentone-isoflurane that had low blood pressure during anesthesia. ANIMALS: 6 healthy Beagles. PROCEDURE: A randomized crossover study was conducted, using the following treatments: saline (0.9% NaCl solution)-saline, saline-carprofen, and carprofen-saline. Saline (0.08 ml/kg) and carprofen (4 mg/kg) were administered IV. The first treatment was administered 30 minutes before induction of anesthesia and immediately before administration of acepromazine (0.1 mg/kg, IM). Anesthesia was induced with thiopentone (25 mg/ml, IV) and maintained with inspired isoflurane (2% in oxygen). The second treatment was administered 30 minutes after onset of inhalation anesthesia. Blood gases, circulation, and ventilation were monitored. Renal function was assessed by glomerular filtration rate (GFR), using scintigraphy, serum biochemical analyses, and urinalysis. Hematologic analysis was performed. Statistical analysis was conducted, using ANOVA or Friedman ANOVA. RESULTS: Values did not differ significantly among the 3 treatments. For all treatments, sedation and anesthesia caused changes in results of serum biochemical and hematologic analyses, a decrease in mean arterial blood pressure to 65 mm Hg, an increase of 115 pmol/L in angiotensin II concentration, and an increase of 100 seconds in time required to reach maximum activity counts during scintigraphy. CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen administered IV before or during anesthesia did not cause detectable significant adverse effects on renal function or results of serum biochemical and hematologic analyses in healthy Beagles with low blood pressure during anesthesia.

Effects of meloxicam on renal function in dogs with hypotension during anaesthesia.

OBJECTIVE: To evaluate the effects of meloxicam on renal function in dogs anaesthetized and rendered hypotensive with acepromazine-thiopental-isoflurane. ANIMALS: Eight healthy beagles, four males and four females, 25.6 +/- 19.3 months old and weighing 12.8 +/- 2.0 kg. MATERIALS AND METHODS: Either meloxicam suspension at a dose of 0.133 mL kg(-1) (0.2 mg kg(-1)) or 0.133 mL kg(-1) saline solution (control), were given by mouth (PO) in a randomized, cross-over fashion. The treatment or control was given 3 hours before anaesthesia. Dogs were sedated with intramuscular acepromazine 0.1 mg kg(-1). Anaesthesia was induced with intravenous thiopental, followed by tracheal intubation and maintenance with isoflurane in oxygen and air, delivered using a semi-closed breathing system. Renal function was quantified using serum biochemistry, urinalysis and glomerular filtration rate measured by scintigraphy. Analysis of variance or Friedman anova were used for statistical analysis. RESULTS: Values (mean +/- SD) for mean arterial blood pressure did not differ significantly between treatments but was low (54 +/- 7 mmHg) during anaesthesia. Glomerular filtration rate did not differ significantly between treatments or over time, and results of urine and serum analysis were within reference ranges after meloxicam treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam caused no adverse effects on renal function when given to healthy dogs anaesthetized and rendered hypotensive with acepromazine, thiopental and isoflurane.