Col10a1 gene expression and chondrocyte hypertrophy during skeletal development and disease

The type X collagen gene, COLIOA1, is specifically expressed by hypertrophic chondrocytes during endochondral ossification. Endochondral ossification is a well-coordinated process that involves a cartilage intermediate and leads to formation of most of the skeleton in vertebrates during skeletogenesis. Chondrocyte hypertrophy is a critical stage of endochondral ossification linking both bone and cartilage development. Given its specific association with chondrocyte hypertrophy, type X collagen plays essential roles in endochondral ossification. It was previously shown that transgenic mice with mutant type X collagen develop variable skeleton-hematopoietic abnormalities indicating defective endochondral ossification, while mutations and abnormal expression of human COLIOA1 cause abnormal chondrocyte hypertrophy that has been seen in many skeletal disorders, including skeletal chondrodysplasia and osteoarthritis. In this review, we summarized the skeletal chondrodysplasia with COLIOA1 gene mutation that shows growth plate defect. We also reviewed recent studies that correlate the type X collagen gene expression and chondrocyte hypertrophy with osteoarthritis. Due to its significant clinical relevance, the type X collagen gene regulation has been extensively studied over the past two decades. Here, we focus on recent progress characterizing the cis-enhancer elements and their binding factors that together confer hypertrophic chondroeyte-specific murine type X collagen gene （CollOal） expression. Based on literature review and our own studies, we surmise that there are multiple factors that contribute to hypertrophic chondrocyte-specific CoHOal expression. These factors include both transactivators （such as Runx2, MEF2C etc.） and repressors （such as AP1, NFATcl, Sox9 etc.）, while other co-factors or epigenetic control of CollOal expression may not be excluded.

DLX5 promotes Col10a1 expression and chondrocyte hypertrophy and is involved in osteoarthritis progression

Osteoarthritis(OA)has been considered non-reversible as articular cartilage wears down with limited repair capacity.Enhanced chondrocyte hypertrophy and increased type X collagen gene(COL10A1)expression have been associated with OA.Therefore,regulators controlling collagen X expression and chondrocyte hypertrophy may play a role in OA intervention.Here,we investigated how Distal-less homeobox 5(DLX5),the distal-less homeobox family member,controls murine Col10a1 gene expression and chondrocyte hypertrophy in chondrogenic cell models and its role in a murine OA model.Through qRT-PCR and Western blot analyses,we detected significantly increased levels of COL10A1 and DLX5 in hypertrophic MCT and ATDC5 cells compared to their proliferative stage.Forced expression of Dlx5 further increases,while knockdown of Dlx5 decreases COL10A1 expression in hypertrophic MCT cells.We have performed dual-luciferase reporter and ChiP assays and demonstrated that DLX5 promotes reporter activity through direct interaction with Col10a1 cis-enhancer.We established a murine OA model and detected markedly increased COL10A1 and DLX5 in the articular cartilage and subchondral bone of the OA mice compared with the controls.Notably,forced overexpression of DLX5 in hypertrophic MCT cells up-regulates RUNX2,and adjacent DLX5 and RUNX2 binding sites have previously been found within the Col10a1 cis-enhancer.Together,our data suggest that DLX5 may cooperate with RUNX2 to control cell-specific Col10a1 expression and chondrocyte hypertrophy and is involved in OA pathogenesis.

Isolation and identification of a novel STR(D17S2204)in the vicinity of NF1 locus

Using a synthetic oligonucleotide （dA-dC）15 as a probe to screen a probe pool made by microdissected human chromosome band 17q11-q12, a DNA fragment containing （CA）16 was isolated, which is a novel short tandem repeat （STR） determined by searching in the GenBank and GDB. It has 8 allelic types with a PIC value of 0.61. The novel STR is conformed with Mendelian segregation according to the linkage analysis of a three-generation neurofibromatosis type Ⅰ （NF1） pedigree. The STR was localized at chromosome band 17q11-q12 in the vicinity of NF1 gene by FISH analysis. The accession number of the STR in GenBank and GDB is G32112 and D17S2204 respectively.