Hormone- and cytokine-mediated signalling in the maintenance of bone balance

Bones form the skeletal framework, enabling movement, mineral balance, and hematopoiesis. Bone remodelling - tightly controlled by hormones, cytokines, and growth factors - is a dynamic process involving different cell types: osteoclasts, osteoblasts, and osteocytes; disrupted remodelling leads to disorders such as osteoporosis, arthritis, rickets, and osteomalacia. This review examines how osteoblast differentiation and bone metabolism are influenced by important hormonal regulators, including parathyroid hormone (PTH), which is the key regulator, followed by the effect of calcitonin, vitamin D, and insulin-like growth factor-1 (IGF-1), cytokines including transforming growth factor-beta, bone morphogenetic proteins, and immune modulators such as cluster of differentiation 40 (CD40)/and its ligand (CD40L). Their signalling pathways converge on key transcription factors - Runt-related transcription factor 2 (RUNX2), Osterix, and osteoprotegerin - and regulators - such as SMAD (suppressor of mothers against decapentaplegic) and mitogen-activated protein kinases (MAPKs) - coordinating osteoblast differentiation, bone matrix deposition, and mineralisation. We distinguish the effects of intermittent versus continuous parathormone administration and emphasise the dual genomic and non-genomic vitamin D actions and factors affecting its receptor expression. The PTH-regulated wingless-related integration site (Wnt)/β-catenin signalling is decisive for osteogenesis, and iPTH and cPTH exert distinct effects on osteoblastogenesis. The signalling pathways - SMAD-independent and SMAD-dependent - that control osteogenesis are analysed. The immune co-receptor CD40 interacts with CD40L to impact both osteoblasts and osteoclasts, linking immune responses and inflammation to bone health alterations. IGF-1 modulates osteoblast development and proliferation through mitogen-activated protein kinase (MEK) pathways. Understanding the molecular interactions among these pathways provides valuable insights into possible therapeutic targets for managing bone regeneration and bone disorders.