Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine

Abstract

Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common form of human myelopathy caused by a compression of the spinal cord by ectopic ossification of spinal ligaments. To elucidate the genetic basis for OPLL, we have been studying the ttw (tiptoe walking; previously designated twy) mouse, a naturally occurring mutant which exhibits ossification of the spinal ligaments very similar to human OPLL (refs 3,4). Using a positional candidate-gene approach, we determined the ttw phenotype is caused by a nonsense mutation (glycine 568 to stop) in the Npps gene which encodes nucleotide pyrophosphatase. This enzyme regulates soft-tissue calcification and bone mineralization by producing inorganic pyrophosphate, a major inhibitor of calcification. The accelerated bone formation characteristic of ttw mice is likely to result from dysfunction of NPPS caused by predicted truncation of the gene product, resulting in the loss of more than one-third of the native protein. Our results may lead to novel insights into the mechanism of ectopic ossification and the aetiology of human OPLL.

Association of a TNAP haplotype with ankylosing spondylitis

“…Several human and mouse diseases with excessive or insufficient bone formation have been related to defects in, respectively, the phosphodiesterases (such as nucleotide pyrophosphatase/phosphodiesterase 1), which produce PPi (11,12), and the phosphatases (such as tissue-nonspecific alkaline phosphatase [TNAP]), which degrade PPi (13)(14)(15). The homozygous ank (progressive ankylosis) mouse has a loss-of-function nonsense mutation in the ank gene that codes for a regulator of PPi export, and these mice develop a condition characterized by pathologic calcium apatite crystal deposition in the synovial and subsynovial spaces, followed by chondro-osteophyte formation and eventual bony ankylosis of the affected joints (16).…”

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

“…Vertebral fusion is a major feature of mice genetically deficient in ENPP1. (59,60) Interestingly, adults with HPP and elevated extracellular PPi levels sometimes manifest seemingly paradoxical calcific periarthritis involving HA deposition in periarticular areas, and also Forestier disease (calcification of the anterior and posterior longitudinal ligaments in the spine). (61) Therefore, the fusion of the posterior elements of the spine of our patient may be from his GACI1 but refractory to EHDP therapy, or perhaps from his EHDP toxicity that mimicked HPP.…”

Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

“…The ank-null mouse phenotype resembles that of the ttw/ttw mouse generated by a truncation in the NPP1 gene (14). Thus, NPP1 and ANK may both contribute to ePPi accumulation in the ECM (13,35,36).…”

“…The naturally occurring "tiptoe-walking" mouse (ttw/ttw mouse) exhibits osteoblast-and chondrocyte-mediated ossification of the spinal ligaments in early life (14). The ttw phenotype results from a nonsense mutation in the gene encoding nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1), also known as plasma cell membrane glycoprotein 1 (PC-1) (14). This ectoenzyme generates ePPi from extracellular ATP (eATP) (see below) (15).…”

“…Interestingly, while NPP1 or TNAP knockout mice exhibit bone mineralization (14,96,97), the double-knockout mice are normal (98). How disruption of this balance leads to pathologic cartilage calcification is discussed below.…”