Cathepsin expression during skeletal development

Söderström, Mirva; Salminen, Heli; Glumoff, Virpi; Kirschke, Heidrun; Aro, Hannu T.; Vuorio, Eero

doi:10.1016/s0167-4781(99)00068-8

Cited by 58 publications

(50 citation statements)

References 49 publications

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“…Consistent with an increase of cathepsin B and L mRNA expression from normal newborn to 5-day-old mouse brains (37) and cathepsin B and L mRNA coexpression in rat brain neurons (38), cathepsin B Ϫ/Ϫ ͞L Ϫ/Ϫ mice exhibit histopathological alterations in the CNS that change rapidly as a function of time. The dramatic course of neurodegeneration in infant cathepsin B Ϫ/Ϫ ͞ L Ϫ/Ϫ knockouts is unlike neuronal loss in, e.g., Munc18-1-deficient mice, which show a failure in prenatal development (39).…”

Section: Discussionmentioning

confidence: 56%

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Felbor

Kessler²,

Mothes³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

305

217

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Cathepsins B and L are widely expressed cysteine proteases implicated in both intracellular proteolysis and extracellular matrix remodeling. However, specific roles remain to be validated in vivo. Here we show that combined deficiency of cathepsins B and L in mice is lethal during the second to fourth week of life. Cathepsin B ؊/؊ ͞L ؊/؊ mice reveal a degree of brain atrophy not previously seen in mice. This is because of massive apoptosis of select neurons in the cerebral cortex and the cerebellar Purkinje and granule cell layers. Neurodegeneration is accompanied by pronounced reactive astrocytosis and is preceded by an accumulation of ultrastructurally and biochemically unique lysosomal bodies in large cortical neurons and by axonal enlargements. Our data demonstrate a pivotal role for cathepsins B and L in maintenance of the central nervous system.

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Section: Discussionmentioning

confidence: 56%

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Felbor

Kessler²,

Mothes³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

305

217

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“…Whether m-calpain is involved in growth plate aggrecanolysis in vivo has not been investigated. Several cathepsins are expressed by hypertrophic chondrocytes (37,38), and in vitro, cathepsins B and D cleave at G 344 ↓ 345 V (39, 40) and F 342 ↓ 343 F (41), respectively, in the aggrecan IGD. Fragments derived from cathepsin cleavage sites have not been detected, and their in vivo relevance has therefore not been confirmed.…”

Section: Discussionmentioning

confidence: 99%

Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair

Little¹,

Meeker²,

Golub³

et al. 2007

J. Clin. Invest.

174

124

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Aggrecan loss from cartilage in arthritis is mediated by aggrecanases. Aggrecanases cleave aggrecan preferentially in the chondroitin sulfate-2 (CS-2) domain and secondarily at the E 373 ↓ 374 A bond in the interglobular domain (IGD). However, IGD cleavage may be more deleterious for cartilage biomechanics because it releases the entire CS-containing portion of aggrecan. Recent studies identifying aggrecanase-2 (ADAMTS-5) as the predominant aggrecanase in mouse cartilage have not distinguished aggrecanolysis in the IGD from aggrecanolysis in the CS-2 domain. We generated aggrecan knockin mice with a mutation that rendered only the IGD resistant to aggrecanases in order to assess the contribution of this specific cleavage to cartilage pathology. The knockin mice were viable and fertile. Aggrecanase cleavage in the aggrecan IGD was not detected in knockin mouse cartilage in situ nor following digestion with ADAMTS-5 or treatment of cartilage explant cultures with IL-1α. Blocking cleavage in the IGD not only diminished aggrecan loss and cartilage erosion in surgically induced osteoarthritis and a model of inflammatory arthritis, but appeared to stimulate cartilage repair following acute inflammation. We conclude that blocking aggrecanolysis in the aggrecan IGD alone protects against cartilage erosion and may potentiate cartilage repair.

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“…Cathepsin B, H, and L proteins and activities (reviewed in Barrett and Kirschke, 1981;Howie et al, 1985;Kirschke et al, 1995;Xing et al, 1998) and mRNAs (Qian et al, 1989;Söderström et al, 1999) have been detected in all tissues and cells examined. Consistent with this ubiquitous pattern of expression, these genes lack the TATA box motifs normally found in highly regulated genes but frequently absent from constitutively expressed genes (Ishidoh et al, 1989a,b;Qian et al, 1991).…”

Section: (I) Properties and Tissue Distributionmentioning

confidence: 99%

Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

Dickinson

2002

Critical Reviews in Oral Biology & Medicine

158

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Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily "housekeeping" functions in the cell. However, mutations in DPP I have now been shown to underlie Papillon-Lefèvre syndrome and pre-pubertal periodontitis. Other cathepsins are involved in tissue-specific functions such as bone remodeling, but relatively little is known about the functions of several recently discovered enzymes. Collectively, CPs participate in multiple host systems that are active in health and in disease. They are involved in tissue remodeling and turnover of the extracellular matrix, immune system function, and modulation and alteration of cell function. Intracellularly, CPs function in diverse processes including normal protein turnover, antigen and proprotein processing, and apoptosis. Extracellularly, they can contribute directly to the degradation of foreign proteins and the extracellular matrix. However, CPs can also participate in proteolytic cascades that amplify the degradative capacity, potentially leading to pathological damage, and facilitating the penetration of tissues by cancer cells. We know relatively little regarding the role of human CPs in the oral cavity in health or disease. Most studies to date have focused on the potential use of the lysosomal enzymes as markers for periodontal disease activity. Human saliva contains high levels of cystatins, which are potent CP inhibitors. Although these proteins are presumed to serve a protective function, their in vivo targets are unknown, and it remains to be discovered whether they serve to control any human CP activity.

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Cathepsin expression during skeletal development

Cited by 58 publications

References 49 publications

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair

Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease

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