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

Abstract

Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

Differentially expressed genes in autosomal dominant osteopetrosis type II osteoclasts reveal known and novel pathways for osteoclast biology

“…The ADO II patients had a total of six different CLCN7 mutations, half of them localized in the C-terminal domain of the protein (Figure 1a). 33 The most frequent mutations responsible for ADO II 10,23 were also represented in our patient group: five related patients had the p.G215R mutation and three unrelated patients the p.R767W mutation. All the patients had a higher than normal (2-5 U/ml) serum TRAP level, with values ranging from 5.3 to 60.9 U/ml (mean value 33.9 ± 9.3 U/ml) (Figure 1b).…”

Osteopetroses, emphasizing potential approaches to treatment

“…There is a very high fracture rate in recessive patients due to poor quality of the non-remodeled bone (3)(4)(5)7). Moreover, these fractures show defective healing.…”

“…Mutations in the gene coding for carbonic anhydrase tend instead to result in a more moderate phenotype, but with cognitive disabilities, as well as other morbidities (6). The dominant form of osteopetrosis, due to dominant negative mutations in the CLCN7 gene, can result in mild, moderate, but also severe disease, although with less infirmities than autosomal recessive forms (7)(8)(9)(10)(11)(12).…”

How rare bone diseases have informed our knowledge of complex diseases

“…Interestingly, the ADO I form presents with a more generalized sclerosis (not the bone-within-bone typical of ADO II), which is especially pronounced in the cranial vault, and has been shown to be due to a number of different mutations in LRP5. 72,85 The fact that a bone formation gene/pathway, which principally acts in the osteoblast lineage, calls into question whether ADO I is correctly associated with osteopetrosis? Studies in mice and bone cell lines [86][87][88][89][90][91][92][93] have shown that Wnt/b-catenin signaling in osteoblasts/osteocytes controls the expression regulators of osteoclastogenesis (for example, osteoprotegerin and RANKL).…”

“…Studies in mice and bone cell lines [86][87][88][89][90][91][92][93] have shown that Wnt/b-catenin signaling in osteoblasts/osteocytes controls the expression regulators of osteoclastogenesis (for example, osteoprotegerin and RANKL). Thus while ADO I has the appearance of an osteopetrotic condition, 85 the primary defect is acting at the osteoblast/ osteocyte cell level, which begs the question of how best to classify the disease. Given the genetic basis of ADO I, perhaps it should be more appropriately categorized as an osteosclerotic phenotype as suggested by de Vernejoul.…”