TAM receptors control actomyosin dynamics in osteoclasts via RHOA-COFILIN-MYOSIN II signaling

Abstract

The TAM family of receptor tyrosine kinases were recently identified to regulate bone homeostasis by controlling osteoblasts and bone formation. Despite extensive knowledge of TAM receptor function in the mononuclear phagocyte system, the role of TAM receptors in osteoclasts remains largely unknown. Here, we identify a physiological regulatory system including MERTK and TYRO3 in osteoclasts controlling RHOA-ROCK-COFILIN/Myosin II signaling, thereby antagonistically regulating osteoclast-mediated bone remodeling to maintain bone homeostasis. Myeloid-specific lysozyme M-mediated deletion of Mertk led to increased bone mass in mice. In early stages of RANKL-induced osteoclast differentiation MERTK promotes amoeboid migration mode in osteoclast precursor cells by inducing RHOA-COFILIN-MLC2 pathway leading to increased osteoclast formation. In contrast, TYRO3 inhibits RHOA-ROCK signaling in osteoclast precursor cells thereby inhibiting these processes. Furthermore, we unraveled an inhibitory role of MERTK as well as TYRO3 in osteoclast differentiation and function. In line with this, mice with cathepsin K-mediated deletion of Mertk and Tyro3 exhibited an osteoporotic bone phenotype. We found that osteoclast precursor cell morphology dictates its fusion capacity and identified MERTK as a negative regulator of osteoclast fusion. In multinucleated cells, deletion of Mertk inhibits actin ring formation by mediating central actomyosin contraction and inactivation of COFILIN. In contrast, spatially well-ordered RHOA activation at adhesion structures, induced by loss of Tyro3, improves osteoclast biomechanotransduction to ameliorate podosome belt formation and enhance osteoclast function. By using a syngeneic breast cancer bone metastasis osteolysis models we identified TYRO3 as a bone protective receptor for osteolytic bone diseases, whereas MERTK represents a pharmacologic accessible target to inhibit osteoclast formation because its stimulatory effects of osteoclast precursors prevail the inhibitory effects on mature osteoclasts. Next to the recently uncovered role of MERTK as a target for osteoanabolic therapy MERTK may represent a one-drug two-target treatment strategy to increase osteoblast function and reduce osteoclast formation for treatments of bone diseases.