Mouse model - spondyloepiphyseal dysplasia congenita and secondary osteoarthritis

Lpk (longpockets): a mouse mutant of the collagen gene Col2a1 showing features of spondyloepiphyseal dysplasia congenita and secondary osteoarthritis (see Esapa, C et al J Bone Miner Res 2012; 27: 413-428).

The Lpk mutation arose in the offspring of a C57BL/6J male treated with N-ethyl N-nitrosourea (ENU).  Mapping and DNA sequencing studies revealed a missense mutation (Ser1386Pro) in the C-propeptide domain of the collagen gene Col2a1. Heterozygotes are viable and fertile, homozygotes die perinatally.

Lpk/+ mice are smaller than wild-type littermates. Most striking is the reduction in length of the long bones especially the humerus.

Histological examinations have revealed abnormalities of the growth plates with flattened epiphyses by 26 days of age in Lpk/+ mice. There is also underdevelopment of secondary ossification centres and disorganisation of the chondrocytes.

Lpk mice have defective processing and inappropriate retention of the mutant COL2A1. By 18.5 dpc, Lpk/+ and Lpk/Lpk mice have fewer and less elaborate collagen fibrils in the extracellular matrix and enlarged vacuoles in the endoplasmic reticulum containing amorphous inclusions. Micro-CT scans revealed decreased bone mineral density and total bone volume with erosions and osteophytes at the joints in 12 week old Lpk/+ mice.

In summary, longpockets is a mouse model for a dominantly inherited form of SEDC associated with osteoarthritis that helps to unravel the in vivo role of the C-propeptide domain of COL2A1 in the assembly and trafficking of type II collagen.

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