Science-in-brief: Recent advances in failure of the blood supply to growth cartilage, osteochondrosis and developmental orthopaedic disease

Abstract

In 1978,¹ Sten-Erik Olsson and his group used the term ‘osteochondrosis’ to describe the focal delay in endochondral ossification that precedes osteochondrosis dissecans (OCD) fragments in joints. In 1986,² a panel led by C. Wayne McIlwraith proposed the term ‘Developmental Orthopaedic Disease’ for conditions commonly diagnosed in young horses, some of which were osteochondrosis-related. Since then, there have been three international meetings on osteochondrosis, most recently in Stockholm in 2008.³ These events tend to be summarised in publications, making them accessible to a wider audience.

Advances have been made since 2008, but due to requirements of the funding source, they are spread on ~40 papers in journals that are variably accessible to equine vets. Ten of the papers (3 equine, 6 porcine, 1 multi-species) were recently gathered in a thesis⁴ because, together, they cover failure of the blood supply to the growth cartilages of long bones,^5-11 cuboidal bones¹² and vertebrae.^{13, 14} The aims of this editorial are to bring that information to the attention of readers of Equine Veterinary Journal, and to summarise the pattern that emerges when different bone types are considered together.

Long bones have a diaphyseal primary ossification centre and secondary ossification centres at either epiphyseal end. Physes are located between primary and secondary centres, whereas each secondary centre is surrounded by epiphyseal growth cartilage, the superficial (towards the joint) portion of which together with articular cartilage is known as the articular-epiphyseal cartilage complex (AECC). Growth cartilage is supplied by perichondrial arterioles organised as anatomical end arteries running inside canals that undergo physiological regression as the cartilage thins.^15-17

In pigs¹⁸ and horses¹⁵ that are heritably predisposed for osteochondrosis, some end arteries fail at the junction between growth cartilage and bone after their midportions are incorporated into the advancing ossification front during growth. Vascular failure leads to ischaemic chondronecrosis at middle depth of the growth cartilage, outside diffusion distance from alternative sources.^{15, 18, 19}

Ischaemic chondronecrosis induces secondary repair responses in growth cartilage, notably proliferation of adjacent vessels¹⁵ and formation of small, separate centres of reparative ossification.²⁰ Repair responses in cartilage are slower than bone growth, thus areas of ischaemic chondronecrosis become surrounded by the ossification front where they cause the focal delay in endochondral ossification that is the definition of osteochondrosis.^{15, 18, 19}

Ischaemic chondronecrosis induces repair responses in bone, including recruitment of chondroclasts capable of removing lesions and formation of granulation tissue capable of intramembranous ossification,²⁰ resulting in spontaneous resolution. The described pathogenesis was experimentally reproduced in pigs by 2004^{19, 21} and in foals by 2013.²²

In 2014, identification of osteochondrosis was translated from histology to conventional CT.^{5, 6} Eighty percent of lesions consisted of multi-lobulated (‘stair-step’)¹⁹ defects in the ossification front.⁵ The blood supply to growth cartilage is the only anatomical component that can explain the distribution and geometry of defects: multiple lobes represent ischaemic chondronecrosis around multiple vessel branches.^{5, 8}

Provided that false-positive structures like nutrient arteries and synovial fossae that develop on a similar timescale to osteochondrosis were ruled out, CT had a 100% (95% CI: 90–100) positive predictive value for ischaemic chondronecrosis.⁵ Lesions arise before joint-specific age thresholds,²³ and longitudinal CT showed that there were multiple peaks in the incidence curves up to the thresholds,⁶ believed to reflect that there are multiple vessels left to incorporate into the ossification front after birth.⁸ Focal defects in the ossification front are pathognomonic for failure of the blood supply to growth cartilage,⁵ but vascular failure can have different aetiologies.⁸

In pigs, it was known that physeal osteochondrosis consists of areas of viable, retained hypertrophic chondrocytes centred on eosinophilic streaks variably described as vessel remnants.³⁵ During translation from histology to CT,^{9, 10} it was confirmed that eosinophilic streaks represent necrotic vessels and that physeal osteochondrosis therefore occurs due to vascular failure.

The blood supply to physes changes after birth. Transphyseal flow is possible in neonates, but in case of the distal femoral physis of pigs³⁶ and horses,³⁷ the transphyseal vessels close around 15 days of age. This has implications for the spread of septic vascular failure⁴ and regional medications.³⁰ Once transphyseal vessels have closed, physes are supplied by the same perichondrial vessels as the AECC:³⁶ the only difference being that the vessels course deep towards the physis rather than superficially towards the AECC. Evidence^{9, 10} supports that physeal vessels fail because their midportions are incorporated into the ossification front towards the deep side of the secondary ossification centre during growth.³⁶

The reason why vascular failure results in retention of viable hypertrophic chondrocytes more than ischaemic chondronecrosis is believed to be that the physis is responsible for bone lengthening.^{4, 9} Physeal growth cartilage is therefore organised in cylindrical units supplied by parallel vessels and collateral diffusion is better following failure relative to the AECC, which is responsible for epiphyseal shaping and has more diverging vessels.^{4, 9}

Physeal osteochondrosis induces secondary responses including formation of OCD-like reparative ossification centres in perichondrium, and ossification past and retrograde into lesions to fill them with bone.^{9, 10} Physes are destined to be replaced with bone, and 100% of lesions are likely to resolve.¹⁰ Despite this, physeal osteochondrosis is considered the main cause of asymmetric lengthening and angular limb deformities (valgus, varus) in pigs.³⁸ Early lesions are common at 3–5 months of age but have resolved when angulation manifests at 8–9 months of age.³⁸ The degree of angulation that develops may depend on lesion size, duration before resolving and adjacent growth rate.¹⁰

Osteochondrosis of vertebral articular process or facet joints is caused by failure of the blood supply to their AECCs⁴⁵ and may progress to OCD, bone cysts and juvenile osteoarthritis,¹³ possibly for similar reasons to why cuboidal bone osteochondrosis progresses to osteoarthritis.^{12, 43, 44}

The ventral two thirds of vertebral bodies have physes and AECC-type growth cartilage bordering onto disk joints,³² rather than synovial joints. Failure of the blood supply to vertebral body AECCs³² may result in formation of multi-lobulated osteochondrosis lesions, OCD-like reparative ossification centres and bone cysts.¹³ However, in pigs, there is more concern over physeal-type osteochondrosis, where failure of vessels in the ventral midline results in ventral vertebral shortening/wedging, dorsal angulation and juvenile kyphosis.^{4, 13, 32} If the affected vessels are located towards the left or right side of the midline, there may be concurrent kyphoscoliosis.^{4, 13, 32}

The dorsal one third of vertebral bodies and the neural arch grow from a pair of physes known as the neuro-central synchondroses, running between and merging with the cranial and caudal vertebral body physes.¹⁴ The neuro-central synchondrosis is poorly described in veterinary literature but well described in human literature,^{46, 47} as it is manipulated in pigs to model scoliosis in children. Unilateral tethering of the neuro-central synchondrosis results in scoliosis, lordosis, rotation and stenosis of the vertebral canal towards the tethered side.⁴⁷ Scoliosis angle depends on age at tethering, number of vertebrae tethered and duration.^{46, 47}

Work has commenced to describe when the neuro-central synchondrosis is open and may be susceptible to vascular failure in the midportion of cervical vertebral bodies in horses up to 14 months old.¹⁴ A spontaneous lesion of ischaemic chondronecrosis has been reported in the midportion of C3 of a foal,⁴⁸ making vascular failure and osteochondrosis a plausible cause of stenosis and spinal cord compression (‘wobbler syndrome’). However, compression is perhaps more likely to occur towards the cranial and caudal ends of vertebrae,⁴⁹ thus closure of the cranial and caudal portions of the neuro-central synchondroses should be studied in older horses from 14 months¹⁴ to 5 years of age.

When failure of the blood supply to the growth cartilages of long bones,^5-11 cuboidal bones^{12, 39} and vertebrae^{13, 14} are considered together,⁴ a pattern emerges:

Depending on diffusion distance to collateral supply, vascular failure causes ischaemic chondronecrosis^{5, 8} or retention of viable, hypertrophic chondrocytes;⁹ both of which result in a focal delay in endochondral ossification, or osteochondrosis.⁴

The thesis work described was conducted at the Norwegian University of Life Sciences, Ås, Norway supported by grants 199598, 244212, 295083 and 344491 from Research Funding for Agriculture and the Food Industry (FFL-JA) via the Research Council of Norway, and H16-47-192/272326 and H20-47-553/323877 from the Swedish-Norwegian Foundation for Equine Research, with contributions from Norsk Hestesenter and Jordbruksavtalen.

The author declares no conflicts of interest.

Kristin Olstad: Conceptualization; funding acquisition; writing – original draft; writing – review and editing; project administration.