Defects in the cartilaginous growth plates of brachymorphic mice.

Abstract

Homozygous brachymorphic (bm/bm) mice are characterized by disproportionately short stature. Newborn bm/bm epiphyseal cartilages are shorter than normal although the cells in the different zones of growth are relatively well organized. The extracellular matrix reacts poorly with stains specific for sulfated glycosaminoglycans. The ultrastructural appearance of the cartilage matrix indicates normal collagen fibrils; however, proteoglycan aggregate granules are smaller than normal and are present in reduced numbers, particularly in the columnar and hypertrophic zones of the growth plate. In addition, a prominent network of fine filaments, which are extractable in 4 M guanidine hydrochloride, are present in the bm/bm cartilage matrix. These findings suggest that a defect affecting the proteoglycan component of cartilage occurs in bm/bm mice.Numerous inherited disorders affect cartilage structure and function in man and other animals. Recently, we have studied cartilage from brachymorphic (bm/bm) mice. This mutant was first described by Lane and Dickie (12), and established by genetic studies as an autosomal recessive condition. Homozygous bm/brn mice are vigorous but have shortened long bones, shortened tails, and dome-shaped skulls. Such findings are consistent with a defect in cartilage development, and Lane and Dickie found the knee joints of 17-24 day old bin~bin mice to be shorter and thicker than normal, although chondrocytes in these epiphyseal growth plates retained good alignment (12).Cartilage is composed predominantly of one cell type, chondrocytes, surrounded by large quantities of extracellular matrix. Of the constituents of the extracellular matrix, two macromolecules, cartilage-type collagen (19, 36) and cartilage-specific proteoglycans (13,22), are synthesized by the differentiated chondrocytes. Ultrastructurally, this extracellular matrix consists of thin, 200-300 ,~ wide cartilage-type collagen fibrils and polygonal matrix granules of precipitated proteoglycan aggregates (1,6,18,25,(33)(34)(35).In examining the cartilaginous epiphyses from bm/bm mice, we have observed alterations in the morphological appearance of the epiphyseal growth plates at different stages of development, as well as differences in the extracellular matrix material which may be related to the abnormalities in tissue development found in this mutant.

Growth Parameters in the Epiphyseal Cartilage of Brachymorphic (bm/bm) Mice

“…These mice therefore offer an opportunity to study the importance of PGs in cartilaginous growth and mineralization. The epiphyseal cartilage in these animals has a considerably reduced height and the morphology of this tissue is less ordered in bm/bm mice than in their heterozygous littermates [18]. Thus, the borders between the zones are less distinct, the columnar orientation of chondrocytes is disturbed, and the mineralization is altered.…”

Expression profile of Papss2 (3′‐phosphoadenosine 5′‐phosphosulfate synthase 2) during cartilage formation and skeletal development in the mouse embryo

“…Brachymorphic (bm) mice have abnormal hepatic detoxification, bleeding times, and postnatal growth (Kurima et al, 1998). The skeletal phenotype of bm mice can be attributed to reduced sulfation of the proteoglycans of the cartilage extracellular matrix (Orkin et al, 1976(Orkin et al, , 1977Schwartz and Domowicz, 2002). It is intriguing that the Papss2 mutation specifically affects postnatal skeletal development.…”

Contribution of PTEN large rearrangements in Cowden disease: a multiplex amplifiable probe hybridisation (MAPH) screening approach

“…The phenotype is inherited as an autosomal recessive mode but bm homozygotes breed normally, have life spans comparable to wild type mice, and are about the same size as normal at birth. The difference in size becomes apparent over the first 4 weeks of life, resulting in a 50% reduction in limb length and a 25% reduction in axial skeletal size 36. Interestingly, the daughter of case 1 is short (148 cm) and has bilateral brachydactyly,14 neither of which are Cowden features.…”