Biomedical subjects

Fayez F Safadi

Publications and source records attributed to Fayez F Safadi.

16 recordsLinked to original sources

PubMed2007

Osteoactivin acts as downstream mediator of BMP-2 effects on osteoblast function.

Our laboratory previously showed that osteoactivin (OA) is a novel, osteoblast-related glycoprotein that plays a role in osteoblast differentiation and function. The purpose of this study was to examine the regulation of OA expression by BMP-2 and the role OA plays as a downstream mediator of BMP-2 effects in osteoblast function. Using primary osteoblast cultures, we tested different doses of BMP-2 on the regulation of OA expression during osteoblast development. To test whether Smad-1 signaling is responsible for BMP-2 regulation of OA expression, osteoblast cultures were transfected with Smad1 siRNA, treated with 50 ng/ml of BMP-2 and analyzed by Western blot. BMP-2 treatment increased OA mRNA and protein expression in a dose-dependent manner and this upregulation was blocked in Smad1 siRNA transfected cultures. We next examined whether the role of OA as a downstream mediator of BMP-2 effects on osteoblast differentiation and matrix mineralization. Osteoblast cultures were transfected with OA antisense oligonucleotides and treated with 50 ng/ml of BMP-2. Cultures transfected with OA antisense oligonucleotides and treated with BMP-2 showed a reduction of OA expression associated with a significant reduction in early and late differentiation markers induced by BMP-2. Therefore, OA acts, at least in part, as a downstream mediator of BMP-2 effects on osteoblast differentiation and matrix mineralization. Our findings suggest that BMP-2 regulates OA expression through the Smad1 signaling pathway. Our data also emphasize that OA protein acts as a downstream mediator of BMP-2 effects on osteoblast differentiation and function.

Animals↗

PubMed2007

Connective tissue growth factor (CTGF) acts as a downstream mediator of TGF-beta1 to induce mesenchymal cell condensation.

Mesenchymal cell (MC) condensation or the aggregation of MCs precedes chondrocyte differentiation and is required for subsequent cartilage formation during endochondral ossification. In this study, we used micromass cultures of C3H10T1/2 cells as an in vitro model system for studying MC condensation and the events important for this process. Transforming growth factor beta1 (TGF-beta1) served as the initiator of MC condensation in our model system and we were interested in determining whether CTGF functions as a downstream mediator of TGF-beta1. CTGF is a matricellular protein that has been found to be expressed in MC condensations and in the perichondrium. Micromass cultures of C3H10T1/2 cells condensed under TGF-beta1 stimulation concomitant with dramatic up-regulation of CTGF mRNA and protein levels. CTGF silencing by either CTGF siRNA or CTGF antisense oligonucleotide approaches showed that TGF-beta1-induced condensation was CTGF dependent. Furthermore, silencing of CTGF expression resulted in significant reductions in cell proliferation and migration, events that are crucial during MC condensation. In addition, up-regulation of Fibronectin (FN) and suppression of Sox9 expression by TGF-beta1 was also found to be mediated by CTGF. Immunofluorescence of developing mouse vertebrae showed that CTGF, TGF-beta1 and FN were co-expressed in condensations of MCs, while Sox9 expression was low at this stage. During subsequent chondrogenesis, Sox9 expression was high in chondrocytes while CTGF expression was limited to the perichondrium. Thus, CTGF is an essential downstream mediator of TGF-beta1-induced MC condensation through its effects on cell proliferation and migration. CTGF is also involved in up-regulating FN and suppressing Sox9 expression during TGF-beta1 induced MC condensation.

Animals↗

PubMed2007

Amelioration of inflammation, angiogenesis and CTGF expression in an arthritis model by a TSP1-derived peptide treatment.

OBJECTIVE: To evaluate the effect of a thrombospondin 1 (TSP1)-derived peptide on inflammation and angiogenesis in an animal model of erosive arthritis and to assess the relationship between TSP1 and connective tissue growth factor (CTGF) in the pathophysiology of rheumatoid arthritis. METHODS: Erosive arthritis in Lewis rats was induced by peptidoglycan-polysaccharide (PG-PS). Animals were divided into four groups: (1) negative control and groups receiving, (2) no treatment, (3) treatment with a TSP1-derived peptide, and (4) treatment with a scrambled peptide. Samples obtained from ankle joint, spleen and liver were studied using histology, histomorphometry, immunohistochemistry and RT-PCR. RESULTS: Histological data indicated that the TSP1-derived peptide treatment decreased neovascularization, leukocyte infiltration and thickening of the synovial lining of the joint, and reduced granuloma formation in the spleen and liver when compared to control groups. Higher concentrations of CTGF and TSP1 proteins were observed in the affected areas of animals which did not receive TSP1-derived peptide treatment. Also, immunofluorescence and RT-PCR analyses showed an increase in CTGF protein expression and regulation, respectively, in the tissues of untreated animals when compared to the TSP1-derived peptide treated animals. By immunofluorescence, TSP1 expression was decreased in the TSP1-derived peptide treated animals. Moreover, macrophage/monocyte-specific staining revealed a decrease in cell infiltration in the articular tissue of the TSP1-derived peptide treated animals. CONCLUSION: Both inflammation and angiogenesis were decreased after TSP1-derived peptide treatment indicating a potential pathway by which TSP1 interaction with neutrophils induces CTGF in RA affected tissues.

Animals↗

PubMed2006

The effect of class a scavenger receptor deficiency in bone.

Class A scavenger receptor (SR-A) is predominantly expressed by macrophages, and because osteoclasts are of monocyte/macrophage lineage, SR-A is of potential interest in osteoclast biology. In addition to modified low density lipoprotein uptake, SR-A is also important in cell attachment and signaling. In this study we evaluated the effect of SR-A deletion on bone. Knock-out animals have 40% greater body weight than wild type. Body composition analyses demonstrated that total lean and fat body mass were greater in knock-out animals, but there was no significant difference in percent fat and lean body mass. Bone mineral density and content were significantly greater in knock-out compared with wild type animals. Micro-computed tomography analyses confirmed that total volume, bone volume as well as trabecular number, thickness, and connectivity were significantly greater in knock-out mice. As expected, trabecular separation was greater in wild type mice. The phenotype appears to be explained by 60% fewer osteoclasts in females and 35% fewer in males compared to wild type mice with a paradoxical increase in nuclei/osteoclast in knock-out animals. Furthermore, there were no differences in adipocyte number and osteoblast number or activity. The addition of the soluble extracellular domain of SR-A to RAW264.7 cells stimulated a concentration-dependent increase in osteoclast differentiation that was receptor activator of nuclear factor-kappaB ligand (RANKL)-dependent. Soluble SR-A had no effect on cell proliferation in the presence of RANKL but stimulated a 40% increase in numbers in the absence of RANKL. We conclude that SR-A plays a role in normal osteoclast differentiation, suggesting a novel role for this receptor in bone biology.

Animals↗

PubMed2006

A peptide from thrombospondin 1 modulates experimental erosive arthritis by regulating connective tissue growth factor.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with leukocyte adhesion to and extravasation through vascular endothelium into synovial tissue. Recent evidence indicates that the thrombospondin 1 gene is up-regulated in patients with RA. We have identified a region within the TSP-1 type 3 repeats that inhibits human neutrophil elastase (HNE) and binds to human neutrophils. The present study was undertaken to investigate the therapeutic benefit of this TSP-1-derived peptide sequence and its effect on connective tissue growth factor (CTGF), a protein involved in fibrotic disorders and in neovascularization, which is a hallmark of RA. METHODS: CTGF gene and protein expression, as well as protein levels of CTGF in the synovium, after treatment with the TSP-1-derived peptide were studied in the peptidoglycan-polysaccharide animal model of erosive arthritis. RESULTS: Peptide treatment prevented joint infiltration and inflammation and was associated with reduced circulating antigen levels of HNE and TSP-1. Additionally, CTGF was up-regulated in this experimental model of RA. Treatment with the TSP-1-derived peptide was associated with down-regulation of the message and protein levels of CTGF. Immunofluorescence studies showed that the mean area fraction of CTGF immunoreactivity in the peptide-treated group of animals was significantly less than that in the untreated group. CONCLUSION: These results document a role for TSP-1 in regulating CTGF gene and protein expression in synovial tissue, suggesting a link with the disease course in this model of RA. This TSP-1-derived synthetic peptide may represent an important template for drug development in RA and other inflammatory conditions associated with neutrophil activation.

Animals↗

PubMed2005

Increase in inflammatory cytokines in median nerves in a rat model of repetitive motion injury.

We examined cytokines in rat median nerves following performance of a high repetition reaching and grasping task at a rate of 8 reaches/min for up to 8 weeks. IL-1alpha, IL-1beta, TNF-alpha, IL-6 and IL-10 were analyzed by immunohistochemistry. Double-labeling immunohistochemistry for ED1, a marker of phagocytic macrophages, was also performed. We found increased immunoexpression of IL-6 by week 3, increases in all 5 cytokines by week 5. This response was transient as all cytokines returned to control levels by 8 weeks of performance of a high repetition negligible force task. Cytokine sources included Schwann cells, fibroblasts and phagocytic macrophages (ED1-immunopositive). These findings suggest that cytokines are involved in the pathophysiology of repetitive motion injuries in peripheral nerves.

Analysis of Variance↗

PubMed2005

Analysis of rat calvaria defects implanted with a platelet-rich plasma preparation: histologic and histometric observations.

OBJECTIVES: It has been suggested that degranulating platelet alpha-granules release growth factors having a potential to modulate bone formation. The objective of this study was to evaluate the osteoconductive potential of a platelet-rich plasma (PRP) preparation. METHODS: Thirty adult male Sprague-Dawley rats were used. The PRP preparation was obtained from 10 ml of whole blood drawn from one age-matched donor rat. The preparation was processed by gradient density centrifugation and stored at -80 degrees C until use. Using aseptic techniques, the PRP preparation soak loaded onto an absorbable collagen sponge (ACS) or ACS alone was surgically implanted into contralateral critical size 6-mm calvaria osteotomies in 18 animals. Twelve animals received ACS versus sham surgery in contralateral defects. Animals were sacrificed at 4 and 8 weeks when biopsies were collected for histologic and histometric analysis. RESULTS: The animals were maintained without adverse events. Bone formation was highly variable in sites receiving PRP and control treatments. Defect bone fill at 4 weeks averaged (+/-SD) 28.8+/-27.4% (PRP/ACS) versus 39.1+/-24.4% (ACS; p=0.2626) and 62.0+/-20.0% (ACS) versus 71.6+/-32.2% (sham surgery; p=0.1088), and at 8 weeks 81.0+/-12.9% (PRP/ACS) versus 64.5+/-28.1% (ACS; p=0.2626) and 75.6+/-34.1% (ACS) versus 74.1+/-24.2% (sham surgery; p=0.7353). Remnants of the ACS biomaterial were observed at both 4 and 8 weeks in sites implanted with PRP/ACS or ACS. CONCLUSIONS: The results suggest that the PRP preparation has a limited potential to promote local bone formation.

Animals↗

PubMed2004

Expression and function of periostin-isoforms in bone.

Periostin was originally identified in MC3T3-E1 osteoblast-like cells. We have identified an isoform of periostin referred to as periostin-like-factor (PLF). It is homologous to other proteins such as fasciclin I (fas I), MPB70, betaIG-H3, and Algal-CAMs. All of these proteins are implicated in regulating cell adhesion. PLF and the other isoforms of periostin differ in their C-terminal sequences. PLF and periostin differ in two specific regions, between 673 and 699 amino acids (aa) and 785-812 aa. Periostin isoforms are expressed in vivo and in vitro during the stages of osteoblast differentiation and maturation. Their mRNAs are present in pre-osteoblast cells as detected by in situ hybridization, and the proteins are between 86 and 93 kD in size as determined by Western blot analysis. Antisense oligonucleotides and antibodies directed against the isoforms of periostin were used to block the activity of these proteins. In both cases, the levels of osteoblast-specific-differentiation markers were markedly reduced suggesting a role for these proteins in osteoblast differentiation.

Amino Acid Sequence↗

PubMed2003

Expression of connective tissue growth factor in bone: its role in osteoblast proliferation and differentiation in vitro and bone formation in vivo.

Connective tissue growth factor (CTGF) is a secreted, extracellular matrix-associated signaling protein that regulates diverse cellular functions. In vivo, CTGF is expressed in many tissues with highest levels in the kidney and brain. The purpose of this study was twofold; first, to localize CTGF in normal bone in vivo during growth and repair, and second, to examine CTGF expression and function in primary osteoblast cultures in vitro and test its effect on bone formation in vivo. Northern and Western blot analyses confirmed that CTGF is expressed in normal long bones during the period of growth or modeling. In situ hybridization and immunohistochemical analysis demonstrated intense staining for CTGF mRNA and protein in osteoblasts lining metaphyseal trabeculae. Examination of CTGF expression in the fracture callus demonstrated that it was primarily localized in osteoblasts lining active, osteogenic surfaces. In primary osteoblast cultures, CTGF mRNA levels demonstrated a bimodal pattern of expression, being high during the peak of the proliferative period, abating as the cells became confluent, and increasing to peak levels and remaining high during mineralization. This pattern suggests that CTGF may play a role in osteoblast proliferation and differentiation as previously demonstrated for fibroblasts and chondrocytes. Treatment of primary osteoblast cultures with anti-CTGF neutralizing antibody caused a dose-dependent inhibition of nodule formation and mineralization. Treatment of primary osteoblast cultures with recombinant CTGF (rCTGF) caused an increase in cell proliferation, alkaline phosphatase activity, and calcium deposition, thereby establishing a functional connection between CTGF and osteoblast differentiation. In vivo delivery of rCTGF into the femoral marrow cavity induced osteogenesis that was associated with increased angiogenesis. This study clearly shows that CTGF is important for osteoblast development and function both in vitro and in vivo.

Animals↗

PubMed2003

Chronic repetitive reaching and grasping results in decreased motor performance and widespread tissue responses in a rat model of MSD.

This study investigated changes in motor skills and tissues of the upper extremity (UE) with regard to injury and inflammatory reactions resulting from performance of a voluntary forelimb repetitive reaching and grasping task in rats. Rats reached for food at a rate of 4 reaches/min, 2 h/day, and 3 days/week for up to 8 weeks during which reach rate, task duration and movement strategies were observed. UE tissues were collected bilaterally at weekly time points of 3-8 weeks and examined for morphological changes. Serum was tested for levels of interleukin-1alpha (IL-1) protein. The macrophage-specific antibody, ED1, was used to identify infiltrating macrophages and the ED2 antibody was used to identify resident macrophages. Rats were unable to maintain baseline reach rate in weeks 5 and 6 of task performance. Alternative patterns of movement emerged. Fraying of tendon fibrils was observed after 6 weeks in the mid-forelimb. After 4 weeks, a general elevation of ED1-IR macrophages were seen in all tissues examined bilaterally including the contralateral, uninvolved forelimb and hindlimbs. Significantly more resident macrophages were seen at 6 and 8 weeks in the reach limb. At 8 weeks, serum levels of IL-1alpha increased significantly above week 0. Our results demonstrate that performance of repetitive tasks elicits motor decrements, signs of injury and a cellular and tissue responses associated with inflammation.

Animals↗

PubMed2003

Median nerve trauma in a rat model of work-related musculoskeletal disorder.

Anatomical and physiological changes were evaluated in the median nerves of rats trained to perform repetitive reaching. Motor degradation was evident after 4 weeks. ED1-immunoreactive macrophages were seen in the transcarpal region of the median nerve of both forelimbs by 5-6 weeks. Fibrosis, characterized by increased immunoexpression of collagen type I by 8 weeks and connective tissue growth factor by 12 weeks, was evident. The conduction velocity (NCV) within the carpal tunnel showed a modest but significant decline after 9-12 weeks. The lowest NCV values were found in animals that refused to participate in the task for the full time available. Thus, both anatomical and physiological signs of progressive tissue damage were present in this model. These results, together with other recent findings indicate that work-related carpal tunnel syndrome develops through mechanisms that include injury, inflammation, fibrosis and subsequent nerve compression.

Animals↗

PubMed2003

Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development.

Coordinated production and remodeling of the extracellular matrix is essential during development. It is of particular importance for skeletogenesis, as the ability of cartilage and bone to provide structural support is determined by the composition and organization of the extracellular matrix. Connective tissue growth factor (CTGF, CCN2) is a secreted protein containing several domains that mediate interactions with growth factors, integrins and extracellular matrix components. A role for CTGF in extracellular matrix production is suggested by its ability to mediate collagen deposition during wound healing. CTGF also induces neovascularization in vitro, suggesting a role in angiogenesis in vivo. To test whether CTGF is required for extracellular matrix remodeling and/or angiogenesis during development, we examined the pattern of Ctgf expression and generated Ctgf-deficient mice. Ctgf is expressed in a variety of tissues in midgestation embryos, with highest levels in vascular tissues and maturing chondrocytes. We confirmed that CTGF is a crucial regulator of cartilage extracellular matrix remodeling by generating Ctgf(-/-) mice. Ctgf deficiency leads to skeletal dysmorphisms as a result of impaired chondrocyte proliferation and extracellular matrix composition within the hypertrophic zone. Decreased expression of specific extracellular matrix components and matrix metalloproteinases suggests that matrix remodeling within the hypertrophic zones in Ctgf mutants is defective. The mutant phenotype also revealed a role for Ctgf in growth plate angiogenesis. Hypertrophic zones of Ctgf mutant growth plates are expanded, and endochondral ossification is impaired. These defects are linked to decreased expression of vascular endothelial growth factor (VEGF) in the hypertrophic zones of Ctgf mutants. These results demonstrate that CTGF is important for cell proliferation and matrix remodeling during chondrogenesis, and is a key regulator coupling extracellular matrix remodeling to angiogenesis at the growth plate.

Animals↗

PubMed2003

Repetitive, negligible force reaching in rats induces pathological overloading of upper extremity bones.

UNLABELLED: Work-related repetitive motion disorders are costly. Immunohistochemical changes in bones resulting from repetitive reaching and grasping in 17 rats were examined. After 3-6 weeks, numbers of ED1+ macrophages and osteoclasts increased at periosteal surfaces of sites of muscle and interosseous membrane attachment and metaphyses of reach and nonreach forelimbs. These findings indicate pathological overloading leading to inflammation and subsequent bone resorption. INTRODUCTION: Sixty-five percent of all occupational illnesses in U.S. private industry are attributed to musculoskeletal disorders arising from the performance of repeated motion, yet the precise mechanisms of tissue pathophysiology have yet to be determined for work-related musculoskeletal disorders. This study investigates changes in upper extremity bone tissues resulting from performance of a voluntary highly repetitive, negligible force reaching and grasping task in rats. MATERIALS AND METHODS: Seventeen rats reached an average of 8.3 times/minute for 45-mg food pellets for 2 h/day, 3 days/week for up to 12 weeks. Seven rats served as normal or trained controls. Radius, ulna, humerus, and scapula were collected bilaterally as follows: radius and ulna at 0, 3, 4, 5, 6, and 12 weeks and humerus and scapula at 0, 4, and 6 weeks. Bones were examined for ED1-immunoreactive mononuclear cells and osteoclasts. Double-labeling immunohistochemistry was performed for ED1 (monocyte/macrophage lineage cell marker) and TRACP (osteoclast marker) to confirm that ED1+ multinucleated cells were osteoclasts. Differences in the number of ED1+ cells over time were analyzed by ANOVA. RESULTS: Between 3 and 6 weeks of task performance, the number of ED1+ mononuclear cells and osteoclasts increased significantly at the periosteal surfaces of the distal radius and ulna of the reach and nonreach limbs compared with control rats. These cells also increased at periosteal surfaces of humerus and scapula of both forelimbs by 4-6 weeks. These cellular increases were greatest at muscle attachments and metaphyseal regions, but they were also present at some interosseous membrane attachments. The number of ED1+ cells decreased to control levels in radius and ulna by 12 weeks. CONCLUSIONS: Increases in ED1+ mononuclear cells and osteoclasts indicate that highly repetitive, negligible force reaching causes pathological overloading of bone leading to inflammation and osteolysis of periosteal bone tissues.

Animals↗

PubMed2003

Anti-osteoactivin antibody inhibits osteoblast differentiation and function in vitro.

Osteoactivin (OA) is a novel protein identified by mRNA differential display using bone from osteopetrotic versus normal rats. Bioinformatic analysis showed that OA cDNA has an open reading frame of 1716 bp encoding a protein of 572 aa, the first 21 aa constitute a signal peptide. OA sequence analysis also demonstrated 13 putative N-glycosylation sites suggestive of a heavily glycosylated protein. In this study, we localized OA protein in primary osteoblast culture by immunofluorescent staining and Western blot analysis. Primary osteoblast cultures pass through three stages: proliferation from day 1 to 7, matrix formation from day 7 to 14, and matrix mineralization from day 14 to 21. OA protein was detected at all stages examined, with maximal expression at 3 weeks when osteoblasts are terminally differentiated. Using the Chariot transfection reagent as a vehicle to deliver anti-OA antibody into the cells, we demonstrated that anti-OA antibody significantly inhibited osteoblast differentiation markers, including alkaline phosphatase activity, nodule formation, osteocalcin production, and calcium deposition, without affecting cell proliferation or viability. These data suggest that OA is an osteoblast-related protein that plays an important role in the regulation of osteoblast differentiation and function.

Alkaline Phosphatase↗

PubMed2003

The anabolic effects of vitamin D-binding protein-macrophage activating factor (DBP-MAF) and a novel small peptide on bone.

Vitamin D-binding protein-macrophage activating factor (DBP-MAF) has previously been shown to stimulate bone resorption and correct the skeletal defects associated with osteopetrosis in two nonallelic mutations in rats. This same protein and a small fragment of the protein have now been shown to demonstrate an anabolic effect on the skeleton of both newborn and young adult, intact rats. The novel peptide fragment was synthetically produced based on the human amino acid sequence at the site of glycosylation in the third domain of the native protein (DBP). The peptide tested is 14 amino acids in length and demonstrates no homologies other than to that region of DBP. Newborn rats were injected i.p. with saline, peptide (0.4 ng/g body wt.) or DBP-MAF (2 ng/g body wt.) every other day from birth to 14 days of age. On day 16 the rats were euthanized and the long bones collected for bone densitometry by pQCT. After 2 weeks of treatment with either the whole protein (DBP-MAF) or the small peptide, bone density was significantly increased in the treated animals compared to the saline controls. Young adult female rats (180 grams) were given s.c. injections of saline or peptide (0.4 ng/g body wt. or 5 ng/g body wt.) every other day for 2 weeks; 2 days after the final injections, the rats were euthanized and the femurs and tibias collected for bone densitometry. Both doses of the peptide resulted in significant increases in bone density as determined by pQCT. Young adult rats were injected locally with a single dose of the peptide (1 microg) or saline into the marrow cavity of the distal femur. One week after the single injection, the bones were collected for radiographic and histological evaluation. The saline controls showed no evidence of new bone formation, whereas the peptide-treated animals demonstrated osteoinduction in the marrow cavity and osteogenesis of surrounding cortical and metaphyseal bone. These data suggest that DBP-MAF and the synthetic peptide represent therapeutic opportunities for the treatment of a number of bone diseases and skeletal disorders. Systemic administration could be used to treat osteoporosis and a number of other osteopenias, and local administration could be effective in fractures, bony defect repairs, spinal surgery, and joint replacement.

Anabolic Agents↗

PubMed2002

The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification.

The toothless (tl) mutation in the rat is a naturally occurring, autosomal recessive mutation resulting in a profound deficiency of bone-resorbing osteoclasts and peritoneal macrophages. The failure to resorb bone produces severe, unrelenting osteopetrosis, with a highly sclerotic skeleton, lack of marrow spaces, failure of tooth eruption, and other pathologies. Injections of CSF-1 improve some, but not all, of these. In this report we have used polymorphism mapping, sequencing, and expression studies to identify the genetic lesion in the tl rat. We found a 10-base insertion near the beginning of the open reading of the Csf1 gene that yields a truncated, nonfunctional protein and an early stop codon, thus rendering the tl rat CSF-1(null). All mutants were homozygous for the mutation and all carriers were heterozygous. No CSF-1 transcripts were identified in rat mRNA that would avoid the mutation via alternative splicing. The biology and actions of CSF-1 have been elucidated by many studies that use another naturally occurring mutation, the op mouse, in which a single base insertion also disrupts the reading frame. The op mouse has milder osteoclastopenia and osteopetrosis than the tl rat and recovers spontaneously over the first few months of life. Thus, the tl rat provides a second model in which the functions of CSF-1 can be studied. Understanding the similarities and differences in the phenotypes of these two models will be important to advancing our knowledge of the many actions of CSF-1.

Alternative Splicing↗