Beyond vitamin D: the potential role of ultraviolet B-induced photoproducts (solar metabolome) in bone and muscle health

Dear Editor, we read with great interest the article by Kamal et al. [1], titled “Impact of ultraviolet radiation on bone density and muscle strength in postmenopausal women: a randomized controlled study“ and would like to offer a few mechanistic insights that may broaden the interpretation of their findings.

First, incorporating a control group exposed solely to ultraviolet B (UVB) radiation and comparing it with the group receiving only vitamin D supplementation would enhance the methodological rigor and strengthen the validity of the study’s conclusions. The authors suggest that combining UVB exposure with vitamin D supplementation is more effective than supplementation alone at improving bone mineral density (BMD) and muscle strength [1]. Although this improvement was primarily attributed to a modest yet statistically significant increase in serum vitamin D levels, further exploration of alternative mechanisms is warranted. These findings underscore the broader biological activity of UVB exposure beyond classical vitamin D metabolism, suggesting a need to reevaluate its systemic endocrine and paracrine effects.

UVB not only induces cutaneous synthesis of vitamin D₃ but also generates a variety of non-canonical photoproducts, including lumisterol₃ and tachysterol₃, along with their hydroxylated derivatives. Traditionally considered biologically inactive, these compounds are increasingly recognized as “less-active analogs”, capable of further hydroxylation, either enzymatically or through continued UVB exposure, subsequently entering the systemic circulation [2]. The presence of hydroxylumisterol derivatives, detected in human serum at nanomolar concentrations following UVB exposure, suggests a potential physiological role [2]. Although these compounds exhibit lower affinity and transcriptional potency for the vitamin D receptor compared with 1,25-dihydroxyvitamin D₃, their broader nuclear receptor interactions are noteworthy [2].

Tachysterol₃, in particular, interacts with a range of other nuclear receptors, including peroxisome proliferator-activated receptor gamma (PPARγ), aryl hydrocarbon receptor (AhR), retinoic acid receptor-related orphan receptors alpha (RORα) and ROR gamma (RORγ), and liver X receptor beta (LXRβ) [2]. This diverse receptor engagement may represent an evolutionarily conserved, redundant signaling network aimed at maintaining musculoskeletal health under variable levels of sunlight exposure. Beyond their local (paracrine) roles in the skin, these metabolites may exert systemic actions because of their presence in the circulation.

PPARγ, which is expressed in skeletal muscle, enhances insulin sensitivity and regulates glucose metabolism. It also promotes oxidative fiber formation and intramuscular fat deposition in porcine skeletal muscle cells [3], with the oxidative fiber potentially accounting for observed gains in muscle strength. Additionally, tachysterol₃ and its hydroxyderivatives have been shown to exert agonistic effects on the AhR, a pathway implicated in muscle mass preservation and contractility [4]. LXRβ, another target of these photoproducts, suppresses osteoclast differentiation and activity, and improving BMD [5].

The inverse agonist activity of these photoproducts on RORα and RORγ may also affect skeletal homeostasis [2]. However, studies investigating the role of RORα in bone biology have yielded mixed results. Some researchers have suggested that RORα promotes osteogenic differentiation and bone formation, whereas others have indicated that its transient overexpression inhibits osteocalcin transcription, counteracting osteogenesis. These discrepancies may reflect differences in the timing and magnitude of RORα expression, suggesting a context-dependent role in bone remodeling.

In conclusion, further research is warranted to elucidate the independent contributions of these non-canonical vitamin D photoproducts to musculoskeletal outcomes and determine whether UVB-based interventions can be safely optimized to harness their biological potential. In this context, we propose referring to these compounds as the solar metabolome, representing a systemic network of sunlight-derived endocrine modulators.