The Src tyrosine kinase has been implicated in a wide variety of signal transduction pathways, yet despite the nearly ubiquitous expression of c-src, src−/− mice show only one major phenotype-osteopetrosis caused by an intrinsic defect in osteoclasts, the cells responsible for resorbing bone. To explore further the role of Src both in osteoclasts and other cell types, we have generated transgenic mice that express the wild-type and mutated versions of the chicken c-src proto-oncogene from the promoter of tartrate resistant acid phosphatase (TRAP), a gene that is expressed highly in osteoclasts. We demonstrate here that expression of a wild-type transgene in only a limited number of tissues can fully rescue the src−/− phenotype. Surprisingly, expression of kinase-defective alleles of c-src also reduces osteopetrosis in src−/− animals and partially rescues a defect in cytoskeletal organization observed in src−/− osteoclasts. These results suggest that there are essential kinase-independent functions for Src in vivo. Biochemical examination of osteoclasts from these mice suggest that Src may function in part by recruiting or activating other tyrosine kinases.
Phosphorylation of the N-terminal domain of Jun by the Jun kinases (JNKs) modulates the transcriptional activity of AP-1, a dimeric transcription factor typically composed of c-Jun and c-Fos, the latter being essential for osteoclast differentiation. Using mice lacking JNK1 or JNK2, we demonstrate that JNK1, but not JNK2, is specifically activated by the osteoclast-differentiating factor RANKL. Activation of JNK1, but not JNK2, is required for efficient osteoclastogenesis from bone marrow monocytes (BMMs). JNK1 protects BMMs from RANKL-induced apoptosis during differentiation. In addition, BMMs from mice carrying a mutant of c-Jun phosphorylation sites (JunAA/JunAA), as well as cells lacking either c-Jun or JunD, which is another JNK substrate, revealed that c-Jun phosphorylation and c-Jun itself, but not JunD, are essential for efficient osteoclastogenesis. Moreover, JNK1-dependent c-Jun phosphorylation in response to RANKL is not involved in the anti-apoptotic function of JNK1. Thus, these data provide genetic evidence that JNK1 activation modulates osteoclastogenesis through both c-Jun-phosphorylation-dependent and -independent mechanisms.
Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is used as a therapy of human RA. We removed the effects of IL-1 from a TNF-mediated inflammatory joint disease by crossing IL-1␣ and -deficient mice (IL-1 ؊/؊ ) with arthritic human TNF-transgenic (hTNFtg) mice. Development of synovial inflammation was almost unaffected on IL-1 deficiency, but bone erosion and osteoclast formation were significantly reduced in IL-1 ؊/؊ hTNFtg mice, compared with hTNFtg mice based on an intrinsic differentiation defect of IL-1-deficient monocytes. Most dramatically, however, cartilage damage was absent in IL-1 ؊/؊ hTNFtg mice. Chimera studies revealed that protection of cartilage is based on the loss of IL-1 on hematopoietic, but not mesenchymal, cells, leading to decreased expression of ADAMTS-5 and MMP-3. These data show that TNF-mediated cartilage damage is completely and TNF-mediated bone damage is partially dependent on IL-1, suggesting that IL-1 is a crucial mediator for inflammatory cartilage and bone degradation.cytokines ͉ rheumatoid arthritis ͉ cartilage
Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-kappaB (NF-kappaB) and extracellular signal-related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-kappaB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-kappaB (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy-induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease.
Objective-To assess the survival rate and functional outcome in elderly patients with space occupying supratentorial infarction who underwent hemicraniectomy compared with those who received medical treatment alone. Methods-All patients older than 55 years with space occupying middle cerebral artery (MCA) infarction treated in our clinic between January 1998 and July 1999 were included in this retrospective analysis. Patients were eligible for decompressive surgery if they were younger than 75 and had no severe comorbidity. Hemicraniectomy was performed regardless of the aVected hemisphere. All patients were followed up for assessment of functional outcome; data were assessed according to the Barthel index and modified Rankin scale and cover a period of 3 to 9 months after infarction. Results-Twelve out of 24 patients underwent hemicraniectomy. Eight patients who were operated on survived; only one patient died of transtentorial herniation, three other deaths were due to medical complications. None of the survivors had a Barthel score above 60 or a Rankin score below 4. Nine out of 12 medically treated patients died of transtentorial herniation, one patient died of medical complications. The two surviving patients had a Barthel score below 60 and a Rankin score of 4. Conclusions-Craniectomy in elderly patients with space occupying MCA infarction improves survival rates compared with medical treatment alone. However, functional outcome and level of independence are poor. Craniectomy in elderly patients should not be performed unless a prospective randomised trial proves beneficial. (J Neurol Neurosurg Psychiatry 2001;70:226-228)
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