Anatomical Distribution of Ochronotic Pigment in Alkaptonuric Mice is Associated with Calcified Cartilage Chondrocytes a
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ORIGINAL RESEARCH
Anatomical Distribution of Ochronotic Pigment in Alkaptonuric Mice is Associated with Calcified Cartilage Chondrocytes at Osteochondral Interfaces Juliette H. Hughes1 · Craig M. Keenan2 · Hazel Sutherland1,4 · Henry R. Edwards1 · Peter J. M. Wilson1 · Lakshminarayan R. Ranganath3 · Jonathan C. Jarvis4 · George Bou‑Gharios1 · James A. Gallagher1 Received: 3 July 2020 / Accepted: 29 September 2020 © The Author(s) 2020
Abstract 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. The exposed collagen hypothesis suggests that collagen is initially protected from ochronosis, and that ageing and mechanical loading causes loss of protective molecules, allowing pigment binding. Schmorl’s staining has previously demonstrated knee joint ochronosis in AKU mice. This study documents more comprehensively the anatomical distribution of ochronosis in two AKU mouse models (BALB/c Hgd−/−, Hgd tm1a−/−), using Schmorl’s staining. Progression of knee joint pigmentation with age in the two AKU mouse models was comparable. Within the knee, hip, shoulder, elbow and wrist joints, pigmentation was associated with chondrons of calcified cartilage. Pigmented chondrons were identified in calcified endplates of intervertebral discs and the calcified knee joint meniscus, suggesting that calcified tissues are more susceptible to pigmentation. There were significantly more pigmented chondrons in lumbar versus tail intervertebral disc endplates (p = 0.002) and clusters of pigmented chondrons were observed at the insertions of ligaments and tendons. These observations suggest that loading/strain may be associated with increased pigmentation but needs further experimental investigation. The calcified cartilage may be the first joint tissue to acquire matrix damage, most likely to collagen, through normal ageing and physiological loading, as it is the first to become susceptible to pigmentation. Keywords Alkaptonuria · Ochronosis · Calcified cartilage · Chondrocyte · Extracellular matrix · Mouse model Juliette H Hughes and Craig M Keenan have contributed equally.
Introduction
* Juliette H. Hughes [email protected]
Alkaptonuria (AKU; OMIM #203500) is a rare inherited metabolic bone disease caused by deficiency of homogentisate 1,2-dioxygenase (HGD; EC 1.13.11.5) [1]. HGD catalyses the breakdown of homogentisic acid (HGA) to 4-maleylacetoacetic acid in the tyrosine catabolic pathway, and therefore HGD deficiency causes increased HGA in the urine, blood and tissues [2, 3]. Most HGA is excreted but over time some is deposited as a dark pigment in connective tissues, primarily the cartilage of loaded joints. This formation of pigment, probably through oxidat
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