Runx2 deletion in hypertrophic chondrocytes impairs osteoclast mediated bone resorption.

Deletion of Runx2 gene in proliferating chondrocytes results in complete failure of endochondral ossification and perinatal lethality. We reported recently that mice with Runx2 deletion specifically in hypertrophic chondrocytes (HCs) using the Col10a1-Cre transgene survive and exhibit enlarged growth plates due to decreased HC apoptosis and cartilage resorption. Bulk of chondrogenesis occurs postnatally, however, the role of Runx2 in HCs during postnatal chondrogenesis is unknown. Despite limb dwarfism, adult homozygous (Runx2HC/HC) mice showed a significant increase in length of growth plate and articular cartilage. Consistent with doubling of the hypertrophic zone, collagen type X expression was increased in Runx2HC/HC mice. In sharp contrast, expression of metalloproteinases and aggrecanases were markedly decreased. Impaired cartilage degradation was evident by the retention of significant amount of safranin-O positive cartilage. Histomorphometry and µCT uncovered increased trabecular bone mass with a significant increase in BV/TV ratio, trabecular number, thickness, and a decrease in trabecular space in Runx2HC/HC mice. To identify if this is due to increased bone synthesis, expression of osteoblast differentiation markers was evaluated and found to be comparable amongst littermates. Histomorphometry confirmed similar number of osteoblasts in the littermates. Furthermore, dynamic bone synthesis showed no differences in mineral apposition or bone formation rates. Surprisingly, three-point-bending test revealed Runx2HC/HC bones to be structurally less strong. Interestingly, both the number and surface of osteoclasts were markedly reduced in Runx2HC/HC littermates. Rankl and IL-17a ligands that promote osteoclast differentiation were markedly reduced in Runx2HC/HC mice. Bone marrow cultures were performed to independently establish Runx2 and hypertrophic chondrocytes role in osteoclast development. The culture from the Runx2HC/HC mice formed significantly fewer and smaller osteoclasts. The expression of mature osteoclast markers, Ctsk and Mmp9, were significantly reduced in the cultures from Runx2HC/HC mice. Thus, Runx2 functions extend beyond embryonic development and chondrocyte hypertrophy by regulating cartilage degradation, osteoclast differentiation, and bone resorption during postnatal endochondral ossification.

Skeletal dysplasias: A radiographic approach and review of common non-lethal skeletal dysplasias.

Skeletal dysplasias are not uncommon entities and a radiologist is likely to encounter a suspected case of dysplasia in his practice. The correct and early diagnosis of dysplasia is important for management of complications and for future genetic counselling. While there is an exhaustive classification system on dysplasias, it is important to be familiar with the radiological features of common dysplasias. In this article, we enumerate a radiographic approach to skeletal dysplasias, describe the essential as well as differentiating features of common non-lethal skeletal dysplasias and conclude by presenting working algorithms to either definitively diagnose a particular dysplasia or suggest the most likely differential diagnoses to the referring clinician and thus direct further workup of the patient.