Roy Morello, Ph.D.

Associate Professor

Ph.D. University of Brescia

Secondary appointments: Division of Genetics, Department of Orthopaedic Surgery
Office (501) 526-4090
Lab (501) 526-4091
RMorello@uams.edu

 

Research interests: In my laboratory we study the function of novel genes, in particular those involved in connective tissue formation, development, homeostasis and disease, with an emphasis on the skeleton. We utilize the power of mouse gene targeting and conditional gene-inactivation techniques to generate ubiquitous or tissue-specific mutations in the mouse. With the use of cell biology, biochemistry, cell microscopy, proteomic and genetic approaches we characterize the phenotype of genetically-modified mice to understand the underlying gene function. The objective is to learn from the animal model and make correlations with relevant aspects of human disease and hence gain mechanistic insights of biological function.

In former studies we characterized the function of the Crtap gene, a member of the Leprecan family of genes. Crtap knock-out mice have dramatic low bone mass and a functional defect in bone forming cells, the osteoblasts. We demonstrated that Crtap forms a complex in the endoplasmic reticulum with two proteins that have enzymatic function and such trimeric complex has essential collagen post-translational modification and chaperone activity. Importantly, while type I collagen mutations in humans cause autosomal dominant Osteogenesis imperfecta (OI – brittle bone disease), we identified CRTAP as the first gene whose mutations cause recessive forms of OI and this led the way to the identification of several new genes causing similar forms of recessive OI. The study of OI pathogenesis utilizing multiple mouse models is actively pursued in my laboratory.

More recent studies, funded by the NIH, aimed at the characterization of another member of the Leprecan family of proteins, Synaptonemal Complex 65 (Sc65, aka P3H4). This protein is highly similar and evolutionarily related to Crtap but it has been poorly studied. With the hypothesis that Sc65 may have retained a similar function to Crtap, we generated two mouse models of Sc65 loss of function and showed that the loss of Sc65 caused low bone mass and skin fragility. Moreover, we also demonstrated that Sc65 is part of a newly described complex in the endoplasmic reticulum together with P3h3 (prolyl 3-hydroxylase 3) and lysyl-hydroxylase 1 (Lh1). This complex is responsible for the hydroxylation of certain collagen triple-helical lysyl residues that are essential for fibrillar collagen cross-linking in the extracellular matrix. We also showed, in collaboration with others, that loss of Sc65 or P3h3 in the mouse phenocopies the loss of Lh1 and hence these mice represent models of the human disease known as Ehlers-Danlos type VIa.

Another ongoing interest in the lab is the study of osteocytes in osteogenesis imperfecta and their potential role in driving high bone turnover. To do this we deleted RANKL expression specifically in osteocytes in the oim/oim mouse model of OI and are preparing a manuscript to describe our findings.

We also have an interest in the role of collagens and collagen-modifying proteins in other tissues, including the lung and the reproductive system and are doing some work also in these directions.

Besides my departmental colleagues, I have close ties with other faculty on campus that work on bone, including Drs. Manolagas, Jilka, Weinstein, O’Brien, Almeida, Zhao, Porter, Iyer, Ambrogini, Ferreira, Xiong and others and have weekly joint meeting with them to discuss ongoing projects and present our work. We also collaborate with other bone and non-bone researchers on campus as well as with colleagues in the US and the rest of the world.

Teaching activities: I currently teach muscle and bone physiology within the Musculoskeletal and Skin Block (MSKSK) to the second year Medical Students and to the Graduate Student within the General Physiology course (PHYO 5103).

RM-4193. A 3D reconstructed micro-CT image of a femur with fracture callus from a 3 month old male oim-Rankl-cKO mouse.

RM-4193. A 3D reconstructed micro-CT image of a femur with fracture callus from a 3 month old male oim-Rankl-cKO mouse.

Phalloidin staining (green) on cortical bone from a 1 month-old female CrtapKO mouse reveals the osteocytes’ delicate dendritic network.

Phalloidin staining (green) on cortical bone from a 1 month-old female CrtapKO mouse reveals the osteocytes’ delicate dendritic network.

TEM images (11500x) of a tenocyte embedded in type I collagen fibrils

TEM images (11500x) of a tenocyte embedded in type I collagen fibrils

Representative Publications

Hudson DM, Weis MA, Rai J, Joeng KS, Dimori M, Lee BH, Morello R, Eyre DR: “P3h3-null and Sc65-null mice phenocopy the collagen lysine under-hydroxylation and cross-linking abnormality of Ehlers-Danlos Syndrome Type VIA”. J Biol Chem. January 23, 2017 – in press.

Heard ME, Besio R, Weis MA, Rai J, Hudson DM, Dimori M, Zimmerman SM, Kamykowski JA, Hogue WR, Swain FL, Burdine MS, Mackintosh SG, Tackett AJ, Suva LJ, Eyre DR, Morello R: “Sc65-null mice provide evidence for a novel endoplasmic reticulum complex regulating collagen lysyl hydroxylation”. PLoS Genet. 12(4); published April 27, 2016.

Gruenwald K, Castagnola P, Besio R, Dimori M, Chen Y, Akel NS, Swain FL, Skinner RA, Eyre DR, Gaddy D, Suva LJ, and Morello R: “Sc65 is a novel endoplasmic reticulum protein that regulates bone mass homeostasis”. J Bone Miner Res. 29(3): 666-75, 2014.

Homan EP, Rauch F, Grafe I, Lietman C, Doll JA, Dawson B, Bertin TK, Napierala D, Morello R, Gibbs R, White L, Miki R, Cohn DH, Crawford S, Travers R, Glorieux FH, and Lee B.: “Mutations in SERPINF1 Cause Osteogenesis Imperfecta Type VI. J Bone Miner Res. 26(12): 2798-803, 2011.

Ben Amor IM, Rauch F, Gruenwald K, Weis M, Eyre DR, Roughley P, Glorieux FH, and Morello R: “Severe Osteogenesis Imperfecta Caused by a Small In-Frame Deletion in CRTAP”. Am J Med Genet. 155A(11): 2865-70, 2011.

Baldridge D, Lennington J, Weis MA, Homan E, Jiang M, Munivez E, Keene DR, Hogue WR, Pyott S, Byers PH, Krakow D, Cohn DH, Eyre DR, Lee B and Morello R: “Generalized Connective Tissue Disease in Crtap-/- Mouse”. PLoS ONE; published May 11, 2010.

Gabbay KH, Bohren KM, Morello R, Bertin TK, Liu J and Vogel P: “Ascorbate Synthesis Pathway: Dual role of Ascorbate in bone homeostasis”. J. Biol. Chem. 2010, 285: 19510-20.

Morello R. and Rauch F.: “Role of Cartilage-associated Protein in Skeletal Development”. Current Osteoporosis Report. Volume 8, Number 2, 2010, 77-83.

Morello R, Bertin TK, Schlaubitz S, Shaw CA, Kakuru S, Munivez E, Hermanns P, Chen Y, Zabel B, and Lee B. “Brachy-syndactyly caused by loss of Sfrp2 function”. J. Cell. Physiol. 2008; 217, 127-137.

Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bachinger HP, Pace JM, Schwarze U, Byers PH, Weis MA, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, and Lee B. “CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive Osteogenesis Imperfecta”. Cell 2006; 127 (2), 291-304.