Anatomical Distribution of Ochronotic Pigment in Alkaptonuric Mice is Associated with Calcified Cartilage Chondrocytes at Osteochondral Interfaces.

Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis), stiffening the tissue. This process over many years leads to a painful and severe osteoarthropathy, particularly affecting the cartilage of the spine and large weight bearing joints. Evidence in human AKU tissue suggests that pigment binds to collagen.

Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of .

CCN2 is a matricellular protein involved in several crucial biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development; however, its role in adult cartilage remains unclear.

Conditional targeting in mice reveals that hepatic homogentisate 1,2-dioxygenase activity is essential in reducing circulating homogentisic acid and for effective therapy in the genetic disease alkaptonuria.

Alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase (HGD) deficiency. Circulating homogentisic acid (HGA) is elevated and deposits in connective tissues as ochronotic pigment. In this study, we aimed to define developmental and adult HGD tissue expression and determine the location and amount of gene activity required to lower circulating HGA and rescue the alkaptonuria phenotype.

Concentric lamellae - novel microanatomical structures in the articular calcified cartilage of mice.

The structure, ultrastructure and function of hyaline articular cartilage (HAC) and subchondral bone (SCB), and their involvement in the pathogenesis of osteoarthritis (OA) have been extensively researched. However, much less attention has been focused on the intervening tissue, articular calcified cartilage (ACC) and its role in the initiation and progression of OA. Using both light microscopy (LM) and transmission electron microscopy (TEM), a study of ACC in wild type (WT) mice, and mice with genetic osteoarthropathies (AKU) was undertaken to further understand the role played by ACC in the early stages of OA.

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice.

Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis.

Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone.

Background: Alkaptonuria (AKU) is a rare metabolic disease caused by deficiency of homogentisate 1,2 dioxygenase, an enzyme involved in tyrosine catabolism, resulting in increased circulating homogentisic acid (HGA). Over time HGA is progressively deposited as a polymer (termed ochronotic pigment) in collagenous tissues, especially the cartilages of weight bearing joints, leading to severe joint disease.

Objectives: To characterise blood biochemistry and arthropathy in the AKU mouse model (Hgd-/-).