The Multifaceted Effects of Osteocytic TGFβ Signaling on the Skeletal and Extraskeletal Functions of Bone

Abstract

Purpose of review: To summarize the fundamental role of transforming growth factor beta (TGFβ) signaling in osteocytes and highlight the physiological and pathophysiological conditions stemming from the deregulation of this pathway in osteocytes.

Recent findings: Osteocytes perform a myriad of skeletal and extraskeletal functions, including mechanosensing, coordinating bone remodeling, local bone matrix turnover, and maintaining systemic mineral homeostasis and global energy balance. Transforming growth factor-beta (TGFβ) signaling, which is crucial for embryonic and postnatal bone development and maintenance, has been found to be essential for several osteocyte functions. There is some evidence that TGFβ might be accomplishing these functions through crosstalk with the Wnt, PTH, and YAP/TAZ pathways in osteocytes, and a better understanding of this complex molecular network can help identify the pivotal convergence points responsible for distinct osteocyte functions. This review provides recent updates on the interwoven signaling cascades coordinated by TGFβ signaling within osteocytes to support their skeletal and extraskeletal functions and highlights physiological and pathophysiological conditions implicating the role of TGFβ signaling in osteocytes.

Keywords: Crosstalk; Endocrine metabolism; Mechanosensitivity; Osteocytes; TGFβ signaling.

Fig. 1

The multifaceted role of osteocytic TGFβ signaling. Osteocytic TGFβ signaling regulates both the conventional skeletal and extraskeletal functions of bone. A In basal conditions, osteocytic TGFβ signaling supports the maintenance of bone quality; B in mechanical stress conditions, osteocytic TGFβ signaling integrates and converts mechanical cues into biological signals (such as RANKL and SOST) that modulate the number and activity of osteoclasts and osteoblasts; C in conditions of mineral metabolic stress, osteocytic TGFβ signaling controls calcium homeostasis by locally lysing and then remodeling perilacunar and canalicular bone matrix (e.g., during lactation); although untested, it is possible that osteocytic TGFβ signaling also functions in an endocrine manner by releasing factors like fibroblast growth factor 23 (FGF23), which will act on the kidney and parathyroid glands to modulate systemic calcium and phosphate homeostasis; D TGFβ signaling can also directly impact osteocyte energetics and affect the production of other cytokines like sclerostin to modulate whole-body energy metabolism through regulation of adipogenesis, muscle activity, and glucose metabolism. Figure created with BioRender.com