MUSCLE AND BONE (L BONEWALD AND M HAMRICK, SECTION EDITORS) Osteogenesis Imperfecta: Muscle–Bone Interactions when Bi-directionally Compromised Charlotte L. Phillips 1,2 & Youngjae Jeong 1 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Purpose of Review Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder of skeletal fragility and more recently muscle weakness. This review highlights our current knowledge of the impact of compromised OI muscle function on muscle– bone interactions and skeletal strength in OI. Recent Findings The ramifications of inherent muscle weakness in OI muscle–bone interactions are just beginning to be elucidated. Studies in patients and in OI mouse models implicate altered mechanosensing, energy metabolism, mitochondrial dysfunction, and paracrine/endocrine crosstalk in the pathogenesis of OI. Compromised muscle–bone unit impacts mechanosensing and the ability of OI muscle and bone to respond to physiotherapeutic and pharmacologic treatment strategies. Summary Muscle and bone are both compromised in OI, making it essential to understand the mechanisms responsible for both impaired muscle and bone functions and their interdependence, as this will expand and drive new physiotherapeutic and pharmacological approaches to treat OI and other musculoskeletal disorders. Keywords Biomechanics . Myostatin . Activin receptor IIB . Musculoskeletal . Crosstalk . Physical activity Muscle–Bone Interactions in Osteogenesis Imperfecta Muscle and bone both regulate and respond bi-directionally to one another [1, 2, 3•]. They are intertwined at multiple levels through biomechanical forces and biochemical paracrine and endocrine factors (circulating osteokines and myokines) orig- inating in one tissue and impacting the other [1, 2, 3•]. The role of muscle and bone interactions is a major area of study in musculoskeletal structure, function, and disease pathogenesis [3•]. This review focuses on the muscle–bone interactions in the pathogenesis and treatment of the hereditary disorder of skeletal fragility, osteogenesis imperfecta, with an emphasis on these interactions as potential therapeutic targets (Fig. 1). Osteogenesis Imperfecta Osteogenesis imperfecta (OI), commonly referred to as “brit- tle bone disease,” is a genetically and clinically heterogeneous heritable connective tissue disorder characterized by de- creased bone mineral density (BMD), skeletal dysplasia, in- creased bone fragility, and more recently inherent muscle weakness [4–6, 7••, 8••]. More than 1500 distinct OI- causing mutations have been identified with approximately 85% due to mutations in the type I collagen genes, COL1A1 and COL1A2, leading to either decreased amounts of normal type I collagen (haplo-insufficient) and/or the production of type I collagen containing either abnormal α1(I) or α2(I) chains (dominant negative) [5, 8••, 9, 10]. In the past 12 years, a flurry of investigations have identified multiple new non- collagenous gene defects responsible for rarer autosomal re- cessive, dominant, and X-linked forms of OI, whose mecha- nisms compromise normal posttranslational processing and molecular folding of type I collagen, collagen fibrillogenesis, osteoblast differentiation and function, and mineralization [4, 5, 8••, 11]. The rapid expansion in the number of OI-causing genes has put the classifications and nosology for OI in flux [4, 5, 12]. For purposes of this review, we will use the tradi- tional classification of OI into the four Sillence groups based This article is part of the Topical Collection on Muscle and Bone * Charlotte L. Phillips phillipscl@missouri.edu 1 Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211, USA 2 Department of Child Health, University of Missouri, Columbia, MO 65211, USA Current Osteoporosis Reports https://doi.org/10.1007/s11914-018-0456-6