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Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαsvariant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

Small leucine rich proteoglycans (SLRPs), including Biglycan, have key roles in many organ and tissue systems. The goal of this article is to review the function of Biglycan and other related SLRPs in mineralizing tissues of the skeleton. The review is divided into sections that include Biglycan’s role in structural biology, signaling, craniofacial and long bone homeostasis, remodeled skeletal tissues, and in human genetics. While many cell types in the skeleton are now known to be affected by Biglycan, there are still unanswered questions about its mechanism of action(s).

Abstract: Using a specially constructed questionnaire, the effect of BRCA test results for the Jewish founder mutations and genetic counseling on womenȁ9s attitudes towards and acceptance of preventive surgeries was evaluated. The subjects consisted of 99 women 43% of whom were found to be carriers as opposed to 57%––non-carriers. After learning of their genetic status, 94% of the carriers and 28% of the non-carriers declared having positively considered the option of preventive oophorectomy. However, only about 25% of the carriers and 4.5% of the non-carriers had positively considered the option of preventive mastectomy. In practice, 78% of the carriers and 18% of the non-carriers who proved to be eligible for these procedures underwent preventive oophorectomy compared with 19% of carriers and 1.8% of non-carriers who underwent preventive mastectomy. Almost all carriers, as well as a majority of the non-carriers, who finally opted for the preventive surgeries did so after learning the result of their genetic test. The different attitudes toward the two surgeries were found to be based on varied beliefs regarding the two procedures. Preventive oophorectomy was perceived as being more acceptable to women than preventive mastectomy both from an attitudinal as well as practical aspect. These differences may be the result of cultural factors, of womenȁ9s trust in the ability of screening tests to prevent morbidity and/or mortality, of the effect of the surgeries on body image and of different counseling protocols.