Cathepsin k

Introduction

Cathepsin K is a member of a large family of lysosomal cysteine proteases, which have been under extensive study over the past decade ^[1][2][3]. Cathepsin enzymes were originally considered general proteases found in the lysosomes of all cell types. However, recent studies have found the expression of Cathepsin K in specific tissue cells ^[3].

Cathepsin K is the most abundant cysteine protease produced by osteoclasts, the multinuclear cells responsible for bone resorption ^[4][5]. This enzyme is also specifically expressed in chondrocytes and is capable of the cleavage of type II collagen, the component of cartilage that provides tensile strength ^[1]. Cathepsin K is has additionally been identified in macrophages and tumor cells and appears capable of the degradation of both apolipoproteins and elastin ^[3][6].

Structure

The active site of cathepsin K consists of three residues: CYS25, HIS162, and ASN182 ^[7].The cleft containing the active site is flanked by two globular domains ^[7][2]. Protease activity is induced by the entrance of the substrate into the active site cleft ^[2][8]. Cathepsin K is called a cysteine protease because the cysteine residue functions as the nucleophile ^[8]. The cysteine residue becomes deprotonated, yielding a negavitely charged thiolate anion, which attacks the substrate peptide bond ^[8]. Proper function of CYS25 requires the formation of an ion pair with the neighboring basic histidine residue ^[8].

Cathepsin K is initially synthesized in its inactive form, pre-procathepsin k, a 37-kDa protein made up of a single peptide chain 329 amino acids in length ^[9][10]. The pre-procathepsin k sequence has three distinct features: a signal peptide, consisting of the first 15 amino acids at the N-terminus; a propeptide, comprising amino acids 16-114; and the main chain, which makes up the final 215 amino acids ending at the C-Terminus ^[11][12]. When the enzyme is activated, the signal peptide and propeptide portions are cleaved to produce the mature cathepsin K protein weighing 27-kDa ^[9][10]. Cathepsin K is active in acidic conditions, within a pH range of 4-6 ^[13].

The signal peptide sequence consists of hydrophobic amino acids, with the exception of one serine residue ^[12]. The propeptide feature contains residues of all 20 standard amino acids, excluding only cysteine and phenylalanine, with the majority comprising leucine (12.1%) and glutamate (11.1%) ^[12]. The activated enzyme, lacking the signal peptide and propeptide sequences, is approximately 54% hydrophillic and 46% hydrophobic, containing 19 negatively charged residues and 26 positively charged residues ^[12]. This net positive charge may contribute to the stability of cathepsin K at low pH ^[14].

Function

Cathepsin K can cleave type I and type II collagen, major components of bone and cartilage matrices, and are highly expressed in osteoclasts and chondroclasts ^[15][1][16]. This enzyme is unique among other cysteine proteases in that it can cleave collagen at multiple sites and in its triple helix ^[13][3]. With facilitation by the protein chondroitin sulfate, cathepsin K forms a complex with other cathepsin K proteins to unravel and cleave the collagen triple helix ^[3].

Cathepsin K is also capable of degrading apolipoproteins, which reside in macrophages and facilitate the efflux of cholesterol from these cells ^[17]. The degradation of apolipoproteins has shown to increase the cholesterol content in macrophages, which is an initial step in arterial plaque formation ^[17].

Cathepsin K seems to contribute to the inflammatory response ^[18][15]. Cathepsin K is expressed by inflammatory cells in response to detected pathogens, possibly in order to cleave pathogenic proteins ^[16].

Disease

Deficiencies in Cathepsin K have been shown to cause pycnodysostosis, characterized by reduced bone resorption, increased bone density, and short stature ^[19]. HIgh activity of cathepsin K has been associated with diseases involving excessive bone and cartilage degeneration, including osteoporosis and rheumatoid arthritis ^[19][15].

Cathepsin K may also take part in atherosclerosis, as high activity of cathepsin K has beed discovered in atherosclerotic lesions ^[2]. Cathepsin K activity can promote the accumulation of cholesterol in macrophages via destruction of apolipoproteins ^[17]. As macrophages become loaded with cholesterol, these cells become foam cells, which are major components of atherosclerotic lesions ^[17]. Apolipoproteins, which facilitate the the removal of cholesterol from macrophages, can be degraded by cathepsin K at a pH of 6 ^[17]. Advanced atherosclerotic cells have a low pH, optimal for cathepsin K activity ^[2][17].

High expression of cathepsin K has been discovered in breast tumor cells, including those metastasized to bone tissue ^[6]. As cathepsin K is capable of extracellular collagen degradation, this protease may function in tumor cells as a means of bone tissue invasion ^[6].

Relevance

Cathepsin K inhibitors have been thought potential treatments for osteoporosis, as high collagenolytic activity by cathepsin K has been identified among patients with this condition ^[4]. However, it has been suggested that the inhibition of Cathespin K may not result in strengthened bone tissue ^[5]. Osteoclasts implement bone resorption in two sequential processes. First, acid is secreted onto the bone surface to demineralize the bone tissue ^[7][4]. Second, the acid secretion and consequential decrease in pH results in the activation of proteases – including cathepsin k – which degrade the bone matrix ^[7][4]. Since demineralization of bone is induced by acid secretion and can continue without cathepsin K, the inhibition of this protease may merely result in the accumulation of weakened bone tissue ^[5][7][4].

As cathepsin K takes part in cartilage degradation by cleavage of type II collagen, the inhibition of this protease could be a treatment for rheumatoid arthritis ^[15]. Articular bone and cartilage degradation, as seen in rheumatoid arthritis, is largely conducted by osteoclasts and synovial fibroblasts, which highly express cathepsin K in inflamed arthritic joint tissue ^[15].

Cathepsin K inhibitors have also been considered for the treatment or prevention of atherosclerosis, as cathepsin K promotes the accumulation of cholesterol in macrophages, leading to foam cell production and atherosclerotic lesions ^[17].

Expression of cathepsin K has been identified in breast cancer tumor cells, as well as metastases embedded in bone tissue ^[6]. Since bone is a common site for tumor metastasis, the inhibition of cathepsin K in tumor cells may prevent or impede the development of malignant bone tumors ^[6].