Skeletal diseases: from mechanism to therapy - Antonella Forlino & Roberta Besio

Antonella Forlino, PI

Email: antonella.forlino@unipv.it

Roberta Besio, PI

Email: roberta.besio@unipv.it

Phone: +39 0382 987235

Antonella Forlino, PI, Full Professor

Roberta Besio, PI, Associate Professor

Francesca Tonelli, Researcher

Sivia Cotti, PhD student

Valentina Daponte, PhD student

Barbara Contento, PhD student

Cecilia Masiero, PhD student

The skeleton is indispensable for determining body size, for allowing movement, for maintenance of the hematopoietic niche and for organ protection. It is mainly constituted by collagen type I and hydroxyapatite minerals, it represents a reservoir of calcium and phosphorus and it is a regulator of several metabolic processes including the control of energy balance. Both rare and common disorders affecting the skeleton are serious burden for human health.

The focus of our research is the molecular, biochemical and functional study of common and genetic diseases affecting the skeleton with the aim to dissect their mechanisms towards the development of innovative therapies. Our laboratory is internationally recognized for the study of the heritable brittle bone disease osteogenesis imperfecta, a family of collagen type I related disorders representing the most common among the rare bone diseases and a perfect model to investigate early onset osteoporosis.

Our skills range from the biochemistry of collagen, to the dissection of protein function, to the development of new therapies for bone disease using cutting edge techniques.

Our main projects are:

1. The generation and the molecular, biochemical and functional characterization of cellular, mouse and zebrafish models for bone diseases, mainly the newest recessive forms of osteogenesis imperfecta
2. The dissection of bone disease mechanisms, to identify common pathways as new targets for innovative therapies
3. The development of bone specific therapeutic approaches.

Our expertise includes: collagen purification and biochemical characterization; primary fibroblast and osteoblast cultures; generation of animal models using CRISPR Cas9; deep phenotyping of the in vitro and in vivo models using OMICS approaches (transcriptomic, proteomic); histomorphometric analysis by high resolution confocal microscopy; characterization of bone properties using microCT; high throughput drug testing in zebrafish and its validation in mice.

Garibaldi N, Besio R, Dalgleish R, Villani S, Barnes AM, Marini JC, Forlino A. Dissecting the phenotypic variability of osteogenesis imperfecta. Dis Model Mech. 2022 May 1;15(5):dmm049398. doi: 10.1242/dmm.049398.

Garibaldi N, Contento BM, Babini G, Morini J, Siciliani S, Biggiogera M, Raspanti M, Marini JC, Rossi A, Forlino A, Besio R. Targeting cellular stress in vitro improves osteoblast homeostasis, matrix collagen content and mineralization in two murine models of osteogenesis imperfecta. Matrix Biol. 2021;98:1-20.

Tonelli F, Cotti S, Leoni L, Besio R, Gioia R, Marchese L, Giorgetti S, Villani S, Gistelinck C, Wagener R, Kobbe B, Fiedler IAK, Larionova D, Busse B, Eyre D, Rossi A, Witten PE, Forlino A. Crtap and p3h1 knock out zebrafish support defective collagen chaperoning as the cause of their osteogenesis imperfecta phenotype. Matrix Biol. 2020;90:40-60.

Besio R, Garibaldi N, Leoni L, Cipolla L, Sabbioneda S, Biggiogera M, Mottes M, Aglan M, Otaify GA, Temtamy SA, Rossi A, Forlino A. Cellular stress due to impairment of collagen prolyl hydroxylation complex is rescued by the chaperone 4-phenylbutyrate. Dis Model Mech. 2019;12(6):dmm038521.

Besio R, Iula G, Garibaldi N, Cipolla L, Sabbioneda S, Biggiogera M, Marini JC, Rossi A, Forlino A. 4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion. Biochim Biophys Acta Mol Basis Dis. 2018;1864(5 Pt A):1642-1652.