Development of an Effective Therapy for Alkaptonuria - Lessons for Osteoarthritis.

Osteoarthritis (OA) is one of the major causes of disability and pain worldwide, yet despite a massive international research effort, no effective disease-modifying drugs have been identified to date. In this review, we put forward the proposition that greater focus on rarer forms of OA could lead to a better understanding of the pathogenesis of more common OA. We have investigated the severe osteoarthropathy of the ultra-rare disease alkaptonuria (AKU).

Reversal of ochronotic pigmentation in alkaptonuria following nitisinone therapy: Analysis of data from the United Kingdom National Alkaptonuria Centre.

Background: Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression.

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial.

Background: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit.

Cartilage biomarkers in the osteoarthropathy of alkaptonuria reveal low turnover and accelerated ageing.

Objective: Alkaptonuria (AKU) is a rare autosomal recessive disease resulting from a single enzyme deficiency in tyrosine metabolism. As a result, homogentisic acid cannot be metabolized, causing systemic increases. Over time, homogentisic acid polymerizes and deposits in collagenous tissues, leading to ochronosis.

Defining the Properties of an Array of -NH-Modified Substrates for the Induction of a Mature Osteoblast/Osteocyte Phenotype from a Primary Human Osteoblast Population Using Controlled Nanotopography and Surface Chemistry.

Accelerating the integration of a joint replacement or the healing of a bone fracture, particularly a complicated non-union fracture, would improve patient welfare and decrease healthcare costs. Currently, an autologous bone graft is the gold standard method for the treatment of complicated non-union fractures, but it is not always possible to harvest such a graft. A proactive highly inductive so-called smart material approach is pertinent in these cases.

c-Fos induction by gut hormones and extracellular ATP in osteoblastic-like cell lines.

It is widely accepted that the c-Fos gene has a role in proliferation and differentiation of bone cells. ATP-induced c-Fos activation is relevant to bone homeostasis, because nucleotides that are present in the environment of bone cells can contribute to autocrine/paracrine signalling. Gut hormones have previously been shown to have an effect on bone metabolism.

Alkaptonuria: An example of a "fundamental disease"--A rare disease with important lessons for more common disorders.

"Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis.

Primary human osteoblast cultures.

Osteoblast cultures can be used to investigate the mechanisms of bone formation, to probe the cellular and molecular basis of bone disease, and to screen for potential therapeutic agents that affect bone formation. Here, we describe the methods for establishing and characterising primary human osteoblast cultures.

Isolation and culture of human osteoblasts.

The skeleton is a dynamic organ that is constantly active throughout life. The highly coordinated actions of bone cells early in life determine the body's shape and form, whilst the constant remodelling (bone resorption followed by an equal amount of bone formation) during adulthood helps to maintain skeletal mass and repair microdamage. When the balance of bone resorption and bone formation becomes unequal, bone diseases, such as osteoporosis, occur.

Involvement of adenosine 5'-triphosphate in ultrasound-induced fracture repair.

Ultrasound (US) accelerates fracture healing; however, the mechanism of this effect remains unclear. Adenosine 5'-triphosphate (ATP) stimulates bone remodeling and is released constitutively from intact osteoblasts; this is a process that is enhanced after mechanical stimulation. We hypothesized that ATP release from osteoblasts is increased after US stimulation and that this leads to accelerated fracture healing.