Severe developmental bone phenotype in ClC-7 deficient mice

Abstract

Bone development is dependent on the functionality of three essential cell types: chondrocytes, osteoclasts and osteoblasts. If any of these cell types is dysfunctional, a developmental bone phenotype can result. The bone disease osteopetrosis is caused by osteoclast dysfunction or impaired osteoclastogenesis, leading to increased bone mass. In ClC-7 deficient mice, which display severe osteopetrosis, the osteoclast malfunction is due to abrogated acidification of the resorption lacuna. This study sought to investigate the consequences of osteoclast malfunction on bone development, bone structure and bone modeling/remodeling in ClC-7 deficient mice. Bones from wildtype, heterozygous and ClC-7 deficient mice were examined by bone histomorphometry and immunohistochemistry. ClC-7 deficient mice were found to have a severe developmental bone phenotype, characterized by dramatically increased bone mass, a high content of cartilage remnants, impaired longitudinal and radial growth, as well as lack of compact cortical bone development. Indices of bone formation were reduced in ClC-7 deficient mice; however, calcein labeling indicated that mineralization occurred on most trabecular bone surfaces. Osteoid deposition had great regional variance, but an osteopetrorickets phenotype, as observed in oc/oc mice, was not apparent in the ClC-7 deficient mice. A striking finding was the presence of very large abnormal osteoclasts, which filled the bone marrow space within the ClC-7 deficient bones. The development of these giant osteoclasts could be due to altered cell fate of the ClC-7 deficient osteoclasts, caused by increased cellular fusion and/or prolonged osteoclast survival. In summary, malfunctional ClC-7 deficient osteoclasts led to a severe developmental bone phenotype including abnormally large and non-functional osteoclasts. Bone formation paremeters were reduced; however, bone formation and mineralization were found to be heterogenous and continuing.

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

“…Along the same line, data from in vitro experiments show that allowing osteoclasts to resorb bone facilitates bone formation by osteoblasts in the resorbed areas (82,83). Furthermore, studies indicate that osteoclasts deposit TRACP on the bone surface leading to recruitment of osteoblasts (84), a finding that correlates with the high levels of TRACP found on the resorbed bone surfaces in ADO patients and other acid secretion-deficient systems (41,85,86) (Fig. 3).…”

“…Studies in the aged ovariectomized rat model using these inhibitors have shown that bone resorption is lowered, while osteoclast numbers and bone formation are maintained (63,73), thereby mimicking the phenotype of the ADO patients and ClC-7-deficient mice (11,41,85,86). Treatment with these inhibitors also resulted in increased BMD and bone strength (63,73), thereby underlining the potential of these molecules.…”

PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis

“…Loss of function of CLCN7 and TCIRG1 -genes that encode key components of the osteoclast acid-secreting machinery -leads to complete abrogation of bone resorption in both humans and mice, in spite of increased osteoclast number; this condition, therefore, is termed osteoclast-rich osteopetrosis (61). Nevertheless, both humans and mice with osteoclast-rich osteopetrosis have increased bone formation (62)(63)(64). In contrast, loss-of-function mutations of RANK lead to complete absence of osteoclasts and "osteoclast-poor" osteopetrosis.…”

Dissociation of Bone Resorption and Bone Formation in Adult Mice with a Non-Functional V-ATPase in Osteoclasts Leads to Increased Bone Strength

“…Increased bone strength has been observed in cortical, but not vertebral bone, of cathepsin K deficient mice [53], and in cortical bone of Ae2 a,b deficient mice [54]. However, these mice also have thickened cortices, as opposed to acid secretion deficient mice, which have very little if any normal cortex [25]. Furthermore, the Ae2 a,b and cathepsin K deficient mice also show less dramatic accumulation of calcified cartilage in the bone marrow cavities [54;55].…”