Chaperoning osteogenesis: new protein-folding disease paradigms

Abstract

Recent discoveries of severe bone disorders in patients with deficiencies in several endoplasmic reticulum chaperones are reshaping the discussion of type I collagen folding and related diseases. Type I collagen is the most abundant protein in all vertebrates and a crucial structural molecule for bone and other connective tissues. Its misfolding causes bone fragility, skeletal deformities and other tissue failures. Studies of newly discovered bone disorders indicate that collagen folding, chaperones involved in the folding process, cellular responses to misfolding, and related bone pathologies may not follow conventional protein folding paradigms. In this review, we examine the features that distinguish collagen folding from that of other proteins and describe findings that are beginning to reveal how cells manage collagen folding and misfolding. We discuss implications of these studies on general protein folding paradigms, unfolded protein response in cells and protein folding diseases. Sans chaperones: osteogenesis choreography gone astrayBone consists of flexible type I collagen fibers and hard hydroxyappatite mineral, making bone material strong yet not brittle. Bone formation (osteogenesis) involves an intricate choreography of specialized cells (Figure 1). Osteoblasts deposit collagen fibers and promote mineralization, osteoclasts resorb older bone and osteocytes act as mechano-sensors that are embedded in bone. These cells interact with each other and are regulated by outside signals from cytokines, hormones and the sympathetic nervous system [1][2][3]. Osteogenesis disorders may be caused by bone cell malfunctions and defects in the collagen matrix.Endoplasmic reticulum (ER) chaperones were brought to the forefront of osteogenesis research by recent discoveries of several new forms of osteogenesis imperfecta (OI). OI is a group of hereditary disorders characterized by bone fractures and deformities [4,5]. Deficiencies in five ER chaperones --CRTAP, P3H1, CYPB, FKBP65, and HSP47 --were found to cause severe OI by leading astray type I collagen folding and osteogenesis choreography [6][7][8][9][10][11][12][13][14][15][16]. The apparent roles of these chaperones in disease pathology, however, presented an unexpected puzzle.Most chaperones assist protein folding by protecting unfolded chains from nonspecific interactions and by catalyzing peptide and disulfide bond isomerization [17][18][19]. However, the functions of CRTAP, P3H1, CYPB, FKBP65, and HSP47 in collagen folding do not Corresponding author: Leikin, S. (leikins@mail.nih.gov).

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta

“…In contrast, Col1a2 oim/+ offspring were more variable and did not show significant changes in femoral geometry. The Col1a2 oim mouse model has compromised bone remodeling and osteoblast maturation and exhibits ER stress, in addition to the observed structural defects (18,19). Cellular defects in osteoblast function may contribute to the less robust geometric response in Col1a2 oim/+ offspring from Mstn tm1Sjl/+ dams.…”

A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis

“…Among these, type I collagen is the most ubiquitous and best characterized. Folding, secretion, and quality control of type I collagen requires multiple steps that may be shared with other types of collagen (3,4). Biosynthesis of procollagen, the biosynthetic precursor molecule of collagen, takes place in the rough endoplasmic reticulum (rER) 2 and is secreted to the extracellular matrix through the Golgi.…”

Classification of osteogenesis imperfecta

“…During these intracellular processes, numerous amino acids are hydroxylated and glycosylated by specific enzymes. In addition, these events are 'assisted' by so called 'molecular chaperones' controlling the proper collagen folding or inducing specific cellular responses-termed endoplasmic-reticulum (ER) stress-to misfolded proteins (reviewed by [14,15]). Subsequently, a procollagen molecule consisting of the core triple helical domain of 1014 amino acids and flanked at each end by globular propeptides is secreted into the pericellular space where the terminal propeptides are removed by specific extracelluar proteinases leading to fibril assembly and the formation of enzymatic crosslinks.…”