Postnatal growth failure of aggrecan deficient mice is due to impaired growth plate chondrogenesis

• Background: Heterozygous Aggrecan (Acan) mutations cause autosomal short stature (ISS) with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (OMIM#165800) in humans. Cartilage matrix deficiency mouse (Acancmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd mice develop postnatal dwarfism with progressing age. However, the underlying cellular and molecular mechanisms causing the growth failure have not been characterized in detail.Objective: To investigate the molecular mechanism of proportionate dwarfism in heterozygous Acan cmd mouse.Methods: Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth, at 1, 3, 6, 12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and femoral growth plates. Cell proliferation was assessed by EdU incorpora-tion and assessed by confocal microscopy. Quantification of percentage matrix area was performed using Image J image analysis software.Results: Heterozygous Acancmd mice were born with a normal body size. However, postnatal growth was reduced resulting in a gradually worsening dwarfism with reduced total body length (p <0.0001) as well as shorter tibial length (p<0.0001) and femoral length (p<0.0001) than their wild-type littermates. Histomorphometric analyses revealed that growth plate chondrocytes were more tightly packed with reduced matrix area (p<0.001) and increased proliferative column density in Acancmd mice compared to wild-type mice. Interestingly, the number of resting zone chondrocytes, proliferative cells per column and hypertropic cells per column were reduced at 1 week of age. In contrast, the size of terminal hypertrophic chondrocytes were normal during early postnatal growth, but reduced at 12 and 24 weeks of age. Despite the differences in growth plate morphology, chondrocyte proliferation was similar in Acan cmd and WT mice. Interestingly, female mice exhibited a more pronounced growth phenotype than the males.Conclusions: Heterozygous Acan cmd mice have a growth disorder that is similar to that in children with heterozygous ACAN mutations in terms of progression with age as well as in magnitude (10-15% smaller). Histomorphometric analyses suggest that the growth failure of aggrecan deficient mice is due to a combination of reduced matrix production and decreased size of the terminal hypertrophic chondrocytes. Further studies will elucidate the pathogenic mechanisms as well as the effect of estrogen on growth in aggrecan haploinsufficiency.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Pediatrik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Pediatrics (hsv//eng)

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