Biology subjects

Farinacci, G.

Publications and source records attributed to Farinacci, G..

3 recordsLinked to original sources

bioRxiv2025

Effects of anti-RANKL, Zoledronate or combination therapy in a mouse model of Fibrous Dysplasia: a preclinical study

Bone fragility and pain are major clinical issues in fibrous dysplasia (FD) of bone, a genetic disorder characterized by increased bone resorption and lytic lesions. Both bisphosphonates (BPs) and denosumab are currently used to treat FD patients, although important concerns remain unsolved. BPs downregulate bone remodeling but their effects on FD lesions and pain are variable. Contrarily, denosumab converts FD tissue into mineralized bone and prevents disease progression, but disease rebound occurs upon treatment withdrawal. The combination of these two drugs may represent an effective and safe strategy for FD treatment. We used a FD mouse model (EF1-GsR201C) to assess whether zoledronate (ZOL) addition to anti-RANKL antibody (RANKL) treatment could preserve the effects of RANKL inhibition after treatment discontinuation. We show that RANKL treatment rapidly reduced bone turnover markers (BTMs) and increased bone mass in affected skeletal segments, but FD lesions recurred shortly after discontinuation. Importantly, RANKL+ZOL combination delayed disease rebound after RANKL withdrawal, as bone density was preserved, BTMs rise was prevented, and no new lesions were observed. ZOL monotreatment increased bone density and reduced BTMs but did not fully halt disease progression. Finally, both RANKL and RANKL+ZOL treatments reduced fracture incidence and ameliorated pain-like behavior in FD mice. These results demonstrate that combining zoledronate with denosumab may effectively treat FD. This strategy could particularly benefit patients with severe, rapidly progressive disease, in which RANKL inhibition would block lesion expansion and reduce bone turnover, while zoledronate would slow down the resumption of the disease and the rebound effect.

pathology↗

bioRxiv2025

Exploring the mechanism and pattern of bone formation during RANKL inhibition in a mouse model of fibrous dysplasia

Fibrous dysplasia (FD) of bone is a genetic fibro-osseous disorder with increased bone remodeling activity. Inhibition of RANKL modifies FD lesions by inducing the replacement of the fibrous tissue with bone. This effect was observed in FD murine models receiving anti-mouse RANKL antibodies or small molecule RANKL inhibitors and in FD patients treated with denosumab. However, in neither case the mechanism and pattern of deposition of the newly formed bone were clarified. We performed radiographic, morphological and molecular analyses on EF1-GsR201C (FD) mice receiving an anti-mouse RANKL antibody. We observed that RANKL inhibition caused a decrease in the expression of genes involved in osteogenesis, osteoclastogenesis, matrix remodeling and osteoblast-osteoclast cross-talk in affected skeletal segments. Nonetheless, intra-lesional bone surfaces were covered by a continuous layer of osteoid, indicating that bone formation was actively ongoing in the pathological tissue in spite of the treatment. Accordingly, all bone surfaces within FD lesions showed calcein labeling which was never detected in the fibrous tissue far from bone. These results indicate that in the absence of RANKL activity, bone formation in FD tissue does not occur diffusely or stochastically. In contrast, it is restricted to bone surfaces where osteoprogenitor cells are orderly recruited from the adjacent fibrosis, progressively converting it into bone. Clinically, this suggests that the volume of pre-treatment bone in FD lesions may be a determinant of the skeletal improvement that individual patients may achieve during the same denosumab treatment course. As a consequence, it may also be a determinant of the severity of the rebound effect that they can experience upon treatment discontinuation.

pathology↗

bioRxiv2024

Bone pain in Fibrous dysplasia does not rely on aberrant sensory nerve sprouting or neuroma formation

Bone pain is a major symptom of many skeletal disorders. Fibrous dysplasia (FD) is a genetic disease with mono or polyostotic skeletal phenotype due to the post-zygotic occurrence of the causative Gs mutation. Bone pain in FD often associates with skeletal deformities and fractures or nerve impingement by the pathological tissue. However, even in the absence of complications, FD patients often complain of a chronic pain that does not correlate with their disease burden. Multiple hypotheses have been made to explain this pain. However, its pathogenetic mechanisms remain, as yet, largely unexplored. In this study, we first demonstrate that the FD mouse model EF1-GsR201C develops a painful-like behavior and an altered response to nociceptive stimuli that, as in FD patients, do not correlate with the severity of their phenotype, thus providing a reliable model to study bone pain in FD. Then, we show that in EF1-GsR201C mice, the overall pattern of skeletal innervation is preserved and that within FD lesions, sensory fibers are variably and focally distributed, mainly at perivascular sites. Finally, we provide the first analysis of a series of human FD bone biopsies showing that sensory nerve fibers are rarely detected within the pathological tissue. These data confirm that bone pain is an intrinsic and reproducible feature of FD. They also show that, albeit sensory nerve fibers are found within FD lesions and may contribute to the unpleasant sensation that accompanies the disease, pathological sensory nerve sprouting or formation of neuromas are not detected in the Gs-mutated skeleton.

pathology↗