Adiponectin signalling in bone homeostasis, with age and in disease

Abstract

Adiponectin is the most abundant circulating adipokine and is primarily involved in glucose metabolism and insulin resistance. Within the bone, osteoblasts and osteoclasts express the adiponectin receptors, however, there are conflicting reports on the effects of adiponectin on bone formation and turnover. Many studies have shown a pro-osteogenic role for adiponectin in in vivo murine models and in vitro: with increased osteoblast differentiation and activity, alongside lower levels of osteoclastogenesis. However, human studies often demonstrate an inverse relationship between adiponectin concentration and bone activity. Moreover, the presence of multiple isoforms of adiponectin and multiple receptor subtypes has the potential to lead to more complex signalling and functional consequences. As such, we still do not fully understand the importance of the adiponectin signalling pathway in regulating bone homeostasis and repair in health, with age and in disease. In this review, we explore our current understanding of adiponectin bioactivity in the bone; the significance of its different isoforms; and how adiponectin biology is altered in disease. Ultimately, furthering our understanding of adiponectin regulation of bone biology is key to developing pharmacological and non-pharmacological (lifestyle) interventions that target adiponectin signalling to boost bone growth and repair in healthy ageing, following injury or in disease.

Fig. 1

Adiponectin signalling. The full-length adiponectin protein can be cleaved into smaller active components, which circulate either as it’s globular domain or as full-length homo-complexes—low molecular weight (LMW) trimers, medium molecular weight (MMW) hexamers or high molecular weight (HMW) oligomers.^– Adiponectin can bind to two classical adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2)^, leading to downstream signalling through several pathways, primarily driving AMP kinase (AMPK) and to a lesser extent activating MAP kinase (MAPK).^– Expression of the oestrogen receptor (ERα) appears to skew adiponectin receptor signalling to primarily trigger the MAPK pathway, which in turn phosphorylates both ERα and transcription factor SP1, altering downstream signalling. AdipoR1 has a higher affinity for the globular domain of adiponectin, whilst AdipoR2 displays an intermediate affinity for all adiponectin isoforms. In addition to the classical adiponectin receptors, HMW and MMW adiponectin can also interact with T-cadherin (cadherin-13; CDH13),^, although the downstream signalling and functional outcomes from these interactions are currently unknown

Fig. 2

Adiponectin regulation of osteoblast and osteoclast migration. Osteoblast progenitors must exit the bone marrow niche to migrate towards the sites of resorption and/or damage. In fate mapping experiments, YFP expressing bone marrow-derived osteoblast precursors migrated to the endosteal surface to replenish osteoblast populations in healthy conditions and also in response to calvarial microfracture. Osteoblast and osteoclast progenitors express CXCR4 and migrate towards high levels of CXCL12 causing them to be retained in the bone marrow. Adiponectin directly and through increasing S1P in the serum, leads to increased osteoblast progenitor migration into the circulation and to bone in health, which is enhanced during injury.^,, In contrast, S1P chemorepels osteoclast progenitors and osteoclasts, leading to decreased migration to damaged sites. This ultimately maintains the balance between resorption (red) and formation (green) to ensure structured bone repair

Fig. 3

Adiponectin signalling in bone. Under healthy conditions, adiponectin supports the proliferation, migration, mineralisation and survival of osteoblasts (green), whilst decreasing osteoclastogenesis and resorption (blue), ultimately leading to bone homeostasis. By contrast, these traits are broadly dysregulated in bones as we age and in patients with obesity or diseases such as rheumatoid arthritis and osteoarthritis: Increases in adiponectin, or changes in environmental cues (including levels of oestrogen) that impact the downstream signalling pathways triggered by adiponectin (e.g. MAPK vs AMPK), pathologically tip the balance in favour of bone resorption and damage (blue) in these conditions