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).