Muscle and Bone: Combating the Evil Side of the Connection

Muscles and bones form intimate relationships at the developmental, anatomical, mechanical, and biochemical level that are all of critical importance for the appropriate formation and function of themusculoskeletal system. Under physiological conditions, pain-free locomotion is facilitated by a proper homeostasis of each tissue and a synergistic and coordinated interaction of the two organ systems. However, disturbances of these tightly regulated processes can cause pain, disability, immobility, and may eventually lead to a lethal fate. Thus, providing more insights into the regulation of muscle-bone interactions under physiological and disease conditions is a very powerful approach for the development of treatments to cure debilitating musculoskeletal maladies. Earliest evidence for the close relationship between muscle and bone is provided by the mesodermal origin of both tissues that give rise to somites. During development, somites differentiate into the dorsal dermomyotome and the ventral sclerotome that eventually form muscle and bone, respectively. While being formed during embryogenesis, muscle and bone develop in a tightly controlledmanner under the influence of a plethora of mechanical and biochemical cues. For instance, intrauterine muscle contraction by the embryo determines the specific circumferential shape of each bone and joint development. During adolescence and in the adult, muscle contraction imposes the greatest load on bone, with a linear relationship between bone mass and muscle size and force. Consequently, loss of bone and muscle mass in the elderly is coupled, leading to osteoporosis and sarcopenia with subsequent falls and fragility fractures. These conditions are among the greatest challenges in today’s musculoskeletal medicine and the development of effective treatments that provide beneficial effects to both bone and muscle is an important goal of ongoing research in the field. Beyond mechanics, muscle and bone are subject to a stringent regulation by soluble ligands and signaling pathways during development and tissue homeostasis in the adult. For instance, canonical Wnt signaling, insulin-like growth factor 1 (IGF-1), transforming growth factor-b (TGF-b), and bone morphogenetic proteins (BMPs), among other pathways, are well established to contribute to the regulation of the differentiation and function of bone and muscle tissue. Downstream of these pathways, cell type–specific transcription factor networks are engaged to control the differentiation and function of bone and muscle cells. Among the signaling pathways that control bone and muscle physiology, the BMP pathway assumes a central role. Historically, in 1965 Marshall R. Urist discovered that the intramuscular implantation of demineralized bone matrix induces the formation of osseous tissue, an observation that led to the discovery of BMPs. Furthermore, this experiment clearly demonstrates that bone can be formed within muscle tissue, provided an appropriate stimulus is present. This finding has been confirmed in vitro using C2C12 myoblasts, which transdifferentiate into matrix-producing osteoblasts upon stimulation with BMP-2 or BMP-4. Although the discovery of BMPs has paved the way for the field of bone regeneration, formation of osseous structures in soft tissue can occur under benign and malignant conditions and may cause tremendous problems for the affected individuals. The most frequent nonmalignant form of heterotopic ossification (HO) is a complication frequently seen after trauma, traumatic brain injury, burns, and major orthopedic surgeries such as hip arthroplasty or acetabular fractures. The rate of disability is variable but patient well-being can be compromised by dysfunction, joint contractures, and severe pain. It has been reported that an activated immune system plays a critical role in the formation of HO by providing local and systemic inflammatory cues that affect oxygen tension and pH and enhances the osteogenic potential of mesenchymal precursor cells through BMP-mediated SMAD signaling, which ultimately leads to heterotopic bone formation. Thus, nonsteroidal anti-inflammatory drugs such as cyclooxygenase (COX)-1 and COX-2 inhibitors and radiation are frequently used in the clinics to prevent HO, whereas a well-planned surgical removal of existing ossifications might alleviate the burden of the patients.